Research team

VIB CMN - Neurodegenerative Brain Diseases Group

Expertise

The VIB Department of Molecular Genetics (DMG) The VIB DMG has a longstanding tradition of combining expertise in molecular genetics and clinical neurology to analyze complex neurological diseases of the central and peripheral nervous system. In the next years, the focus will be on increasing our understanding of the molecular aspects of neurodegenerative processes observed in diseases like neurodegenerative dementia and peripheral neuropathies with the ultimate goal to gather sufficient information to open avenues for translational research and potential therapeutic interventions.

VIB-Studying TLR9 LoF in brain and iPSC of patients with deleterious mutations. 01/10/2021 - 30/09/2023

Abstract

In this project, we aim to investigate the mechanisms underlying immune dysregulation in Alzheimer's disease (AD) caused by genetic mutations in Toll-like receptor 9 (TLR9). In a genetic study, using whole exome sequencing (WES), we identified the missense mutation TLR9 p.E317D co-segregating with the disease status in an early-onset (EO) autosomal dominant AD family. TLR9 is a DNA-sensing receptor expressed in human B cells and in plasmacytoid dendritic cells (pDC) that recognizes unmethylated CpG oligodeoxynucleodides (CpG ODNs) and it is responsible for enhanced uptake and killing of microorganisms as well as the generation of adaptive immune response. We showed that the EOAD co-segregating variant p.E317D decreased the TLR9 CpG-induced signaling efficiency by more than 50%. We aim to study TLR9 loss of function in human brain tissue as well as in iPSC generated from 2 TLR9 p.E317D mutation carriers. We will compare the results to the isogenic control lines obtained by genome editing the mutation to the wild-type residue and we will use a TLR9 full KO cell line to investigate the effect of a complete TLR9 loss of function. We will first optimize the iPSC differentiation into pDC and prove that TLR9 is functionally active. We will then investigate how the TLR9 p.E317D mutation and the total TLR9 loss (TLR9 KO) in the periphery (iPSC-derived pDC cells), affect the function of cell types found in the central nervous system (CNS), i.e., iPSC-derived neurons and microglia in this study. This will shed more light on the mode of action (MoA) of TLR9 mutations in AD etiology. Finally, we will perform single-nuclei RNA sequencing (snRNA-sequencing) on fresh frozen brain tissue of the TLR9 p.E317D mutation carrier, brain tissue of AD patients with known pathogenic PSEN1 mutations and we will compare to neurologically healthy control brain tissues. This will identify subpopulations of disease-related cells disclosing disease related pathways.

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Onset age variability in GRN-associated frontotemporal lobar degeneration: identification of a functional onset age modifier. 01/10/2019 - 30/09/2022

Abstract

Mutations in the granulin gene (GRN) are a major cause of frontotemporal lobar degeneration (FTLD). A striking feature of these patients is the wide onset age variability, which can span up to 40 years within one family. Identifying onset age modifiers is of importance as they might represent targets for disease-delaying therapies. Currently, there are no cures for FTLD patients. The modifiers could also be relevant in the context of disease prognosis and genetic counseling. We have used a family-based approach to identify onset age modifiers, starting from an extended Belgian founder family segregating a GRN mutation. Patients of the family have onset ages ranging from 45 to 80 years. In this family, we have identified a genomic locus that affects the onset age. This project aims to identify the functional onset age modifier gene and variant within this locus, and to extend the findings to international patient cohorts. We will perform a high-throughput screen to prioritize functional variants within the locus, expression analyses on brain material and lymphoblast cell lines, and cellular assays in induced pluripotent stem cell-derived cortical neurons of carriers of the GRN founder mutation to study the effect of candidate modifier genes and variants. We will investigate the modifier variant in extended international patient cohorts. Such a genetic epidemiological characterization will be relevant for possible applications in a clinical setting.

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Molecular research into neurodegenerative brain diseases including Alzheimer disease, Frontotemporal lobar degeneration, Parkinson's disease and related diseases. 20/03/2017 - 31/12/2021

Abstract

Molecular research of neurodegenerative brain diseases aims at understanding the genetics and underlying molecular pathways that are leading to these diseases. This includes genetics and genomics studies of the different disease sub-types of dementia and Parkinson disease. Underlying genetic contributions are examined in familial and sporadic patients, followed-up with functional studies in patient-derived bio-materials to obtain information about the causality and progression of the disease, and to identify target proteins and pathways for pharmaceutical intervention. Identification of genetic factors will also contribute to the clinical diagnosis of patients and to a better understanding of the brain pathological characteristics specific for the different disease sub-types.

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Institutional funds VIB8 2017-2021: VIB-Antwerp Center for Molecular Neurology (CMN). 01/01/2017 - 31/12/2021

Abstract

Het VIB Departement voor Moleculaire Genetica (DMG) beschikt over expertise in de analyse van complexe neurologische en neuropsychiatrische ziekten. Al deze ziekten zijn multifactorieel wat betekent dat hun expressie afhankelijk is van de samenwerking tussen genetische en omgevingsfactoren. In sommige van deze ziekten is het overervingspatroon mendeliaans met gendefecten in één gen. In andere ziekten kan slechts een kleine fractie van patiënten verklaard worden door genetische factoren. In deze groep werden verschillende families geïdentificeerd met een mendeliaanse overerving (= monogenische component). In de meerderheid van de patiënten wordt de expressie van de ziekte gemoduleerd door complexe gen-gen en gen-omgeving interacties. Onze belangrijkste doelstellingen zijn de identificatie van nieuwe moleculaire mechanismen voor het ontstaan van deze ziekten en voor een efficiëntere behandeling van deze ziekten. Wij gebruiken verschillende genetische methoden om genen (causale genen) en risicofactoren (susceptibiliteitspolymorfismen) te identificeren gebaseerd op moleculair genetische en genetisch epidemiologische studies. De bijdrage van een ziektegen wordt geschat in populatie en hospitaal gebaseerde groepen van patiënten in relatie tot andere genen en omgevingsfactoren. De biologische relevantie van mutaties en polymorfismen wordt onderzocht in cellulaire systemen (bvb. stabiele cDNA transfectanten) en in muismodellen. Deze modellen laten ons toe om het effect van deze mutaties en polymorfismen op de normale functie van het genproduct te begrijpen. Bovendien kunnen de geobserveerde biologische fenomenen direct vergeleken worden met deze in patiënten. Tenslotte, kunnen deze modellen gebruikt worden om behandelingswijzen uit te testen. Vandaag zijn er 5 onderzoeksgroepen actief in het departement met elk een professor als groepsleider: Neurodegeneratieve Hersenziekten (Christine Van Broeckhoven PhD DSc), Neurogenetica (Peter De Jonghe MD PhD), Perifere Neuropathieën (Vincent Timmerman PhD), Moleculaire Neurogenomica (Albena Jordanova PhD) en Toegepaste Moleculaire Genomica (Jurgen Del-Favero PhD).

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Research of genetic, clinical and neuropathological characteristics of neurodegenerative brain diseases with focus on Alzheimer's disease and frontotemporale dementia 01/10/2020 - 30/09/2021

Abstract

This funding will be used for the extension of the PhD mandates of Elisabeth Hens and Helena Gossye with one year from October 1st 2020 to September 30th 2021 (third PhD year). Both are PhD students in the group of Professor Christine Van Broeckhoven. Both PhD students are medical doctors and neurology trainees. The main aim of their project is to examine in dept the genotype - phenotype correlation of familial and sporadic patients, carrying causal mutations in genes associated with Alzheimer's disease or frontotemporal dementia. These studies will deliver a better understanding of the clinical profile of these patients which will be helpful in the clinical diagnoses and the inclusion in clinical trials aiming at personalized treatment.

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Investigating the contribution of causal genes in early-onset dementia. 01/11/2018 - 30/04/2019

Abstract

Dementia is a devastating disorder with a wide range of symptoms, such as memory loss, cognitive impairment and changes in behavior, severe enough to affect the everyday life. There are 47 million of people leaving with dementia worldwide and this number will reach 131 million in 2050. As such, dementia represents a social and economic burden for the entire society. The most common subtype of dementia is Alzheimer's disease (AD) which accounts for 50% to 75% of all dementia patients. Important discoveries have led to the identification of genes linked to the AD etiology (APP, PSEN1, PSEN2). Despite these discoveries, which have happened 30 years ago, there is still no treatment available that can cure AD, nor slow its progression. It is therefore imperative to improve treatment and diagnosis and this will be possible through a better understanding of the disease causes. Importantly, there are several mutations in these Alzheimer genes of which the pathogenicity is unknown. Understanding pathogenicity of variants has great implications in the clinical practice, in terms of genetic counseling and inclusion of patients in clinical trials. Besides many efforts, assays to enable a clear discrimination between pathogenic and neutral variants are still missing This project aims to unreveal the contributions of the mutations in these AD genes to the disease etiology. This is a first but essential step towards a more accurate clinical diagnosis and patients follow-up.

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Exploring the role of DPP6 loss and hyperexcitability in neurodegenerative brain diseases. 01/10/2017 - 30/09/2020

Abstract

Using advanced genetic and genomic studies, as well as expression studies in brain tissue of patients and electrophysiological modelling in Xenopus laevis oocytes, we identified dipeptidyl peptidase 6 (DPP6) as novel candidate gene in neurodegenerative brain diseases (NBD) (Cacace et al., Journal of Neurochemistry (2016) 138:231-232 and Cacace et al., under revision). Our results suggested a loss-of-function mechanism leading to the dysregulation of the normal DPP6 function in relation to its molecular partner, the potassium channel Kv4.2. In this project proposal, we plan the follow-up of our genetic findings. We hypothesize that loss of DPP6 could be crucial in alteration of brain network activity and consequentially neuronal hyperexcitability and neurodegeneration. We aim to disentangle this hypothesis using in-vitro studies in both patients' brain tissue and in cellular models, as well as in vivo studies to establish the validity of the DPP6 KO mouse model in NBD. This project aims to understand the entity of pathological consequences of DPP6/Kv4.2 dysregulation in relation to NBDs. The project outcomes will represent a fundamental milestone for novel assumptions on disease mechanism(s). Our final goal is to develop an in-vitro assay for compound testing, with a (long-term) translational application such as the development of (more personalized) preventive/efficacious therapeutic interventions.

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VIB-The role of upstream open reading frames and protein expression regulation in frontotemporal lobar degeneration. 01/01/2016 - 31/12/2018

Abstract

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of conditions caused by degeneration of the frontal and temporal brain lobes. Clinical characteristics generally appear at about 60 years of age and include changes in personality and behavior, language impairment and executive dysfunction. In advanced disease stages, dementia may become apparent. Due to the relatively early average onset age compared to other dementia types, it is the second-most common cause of dementia after Alzheimer disease in the age group below 60 years. Little is known about the underlying disease mechanisms. Often, the disease is transmitted within families indicating that penetrant genetic defects are common. About 50% of FTLD families can be explained by a genetic defect in the protein-coding regions of the genome. In at least a part of the unexplained families, FTLD is likely caused by a defect outside the protein-coding regions resulting in disturbed gene expression. Recent accumulating evidence shows that small open reading frames in noncoding sequences of most genes play a major role in regulating protein production in the cell. Some diseases have been associated with defects in such upstream open reading frames. We will thoroughly evaluate the hypothesis that they also play a role in FTLD. To our knowledge, this study is the first of its kind in FTLD research. It has the potential to lead to novel mechanistic insights in FTLD and to deliver novel biomarkers.

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Coordination of an European Early-Onset Dementia consortium as platform for translation genetic research 01/01/2016 - 31/12/2018

Abstract

This grant finances the coordination activities of the European Early-Onset Dementia (EU EOD) consortium. The EU EOD consortium was founded in 2011 by the P.I. to promote and facilitate translational genetic and clinical research of early-onset dementia (EOD) at the European level. The aim of the consortium is to capitalize on the genetic power of EOD patients combined with the novel –omics technologies that have become available. The consortium unites partners from dementia expert centers covering the fields of neurology, neuropathological, clinical research (biomarkers, neuroimaging) and treatment trials, medical genetics and molecular genetics. The FWO ICA fund supports the coordination and activities of the consortium such as organizing regular meetings between the partners either in conjunction with international conferences or of formal EU EOD consortium annual meetings.

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Deciphering the molecular landscape of Early Onset Parkinson Disease using an integrated approach of exome and transcriptome sequencing. 01/01/2015 - 31/12/2018

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

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Translational research in neurodegenerative dementia and related disorders. 01/01/2015 - 31/12/2017

Abstract

Neurodegenerative dementia such as Alzheimer disease and frontotemporal lobar degeneration will likely pose an increasing social and economic impact on the European and global population due to the ever-increasing mean age of our population. There is a current paucity of effective prophylactic treatments and as such they represent one of the only major classes of widespread diseases with increasing mortality rates in the developed world. Our main goal is to contribute to the understanding of the molecular basis of neurodegenerative brain diseases such as Alzheimer disease and related dementia and to translate this information to clinical practice. We will undertake genome and exome projects to identify novel rare, high penetrant disease mutations in multiplex and nuclear families, as well as genealogically unrelated patients with extreme phenotypes. The entire spectrum of variations will be explored i.e. simple DNA sequence variations as well as complex structural and copy number variations (CNV), coding and noncoding regulatory variations, etc. Our major future strategic research trajectories aim at increasing investment in sampling and biobanking, increasing investment in next generation sequencing and –omics technologies allowing integration of multiple layers of biological information for enhanced gene- and protein discovery, establishing disease-related functional genomics and cell biology and introducing translational research.

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VIB-Identification of novel genetic defects and post-genomic consequences leading to Lewy body brain disease. 01/01/2015 - 31/12/2016

Abstract

Parkinson disease, Lewy body dementia and the Lewy body variant of Alzheimer dementia are members of the Lewy body disorders spectrum. To reduce the steep increase in prevalence of these devastating diseases we urgently need to develop tools for early diagnosis and therapies intervening with the disease processes. To reach that objective we need a profound knowledge of the molecular players and mechanisms underlying these complex brain diseases. Molecular genetic studies have contributed substantially to the current knowledge of the disease processes but known genes only explain a small percentage of the familial patients, suggesting the existence of additional genetic defects. The advent of massive parallel sequencing (MPS) has provided means to accelerate disease gene identification but created a novel challenge of proving the causality of genetic alterations. Therefore, the aim of this project is to unravel the underlying disease mechanisms more efficiently by integrating multiple layers of biological evidence, including those reflecting the biological effects of newly identified genetic alterations. The combined information will deepen our understanding of the disease mechanisms, endorse classification of these complex brain diseases based on the genetic background and guide the establishment of disease-related biomarkers for early detection and diagnosis. It will also guide the establishment of disease-related models applicable the identification and monitoring of novel targeted therapies in the future.

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VIND: Flemish Impulse Funding for Networks for Dementia research. 01/05/2014 - 31/12/2018

Abstract

This project represents a formal research agreement between UA and on the other hand the Flemish Public Service. UA provides the Flemish Public Service research results mentioned in the title of the project under the conditions as stipulated in this contract.

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Research on the Alzheimer's disease. 01/01/2014 - 31/12/2019

Abstract

This project represents a formal research agreement between UA and on the other hand the client. UA provides the client research results mentioned in the title of the project under the conditions as stipulated in this contract.

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Genetic modifiers of onset age in frontotemporal lobar degeneration. 01/01/2014 - 31/12/2017

Abstract

This project aims to study the biological mechanisms acting on onset age modification by focusing on the identification of genes influencing the onset age using the latest molecular genetics technologies. This research will generate valuable novel insights to develop disease-delaying therapies for FTLD and related neurodegenerative disorders.

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Post-genomic profiling and therapeutic targeting of specific and generic neurodegenerative mechanisms. 01/10/2013 - 31/12/2017

Abstract

The primary aim of the proposed research program is to develop an understanding of the quantitative and qualitative post-genomic sequelae of CNS disorders, whose genomic origins have been extensively characterized at the Department of Molecular Genetics and at other Institutions in the VIB, these include: familial Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), frontal temporal lobar degeneration (FTLD), mild cognitive impairment (MCI) and early-onset dementia (EOD).

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    Detection of novel genes for frontotemporal lobar degeneration using whole-genome sequencing. 01/10/2013 - 30/09/2015

    Abstract

    Worldwide, almost 35.6 million people are suffering from dementia, accounting for 3.4% of all deaths in high-income countries. The possibilities for prevention and treatment of dementia are limited and the risk of developing the condition rises steeply with age resulting in an increasing number of patients suffering from this disease. Global population ageing will result in huge increases in the number of patients with dementia, which is estimated to double every 20 years. In Belgium alone, around 163 500 are suffering from dementia. My PhD project is mainly focusing on frontotemporal lobar degeneration (FTLD), which is, after Alzheimer disease, the most common cause of dementia in patients younger than 65 years. FTLD is a clinically heterogeneous group of conditions caused by neuronal degeneration of the frontal and temporal lobes of the brain. Main clinical characteristics include changes in personality and behavior, impairment of language, and executive dysfunction. About 50% of the FTLD patients show familial history of dementia, suggesting that genetic predisposition plays a major role in the etiology of FTLD. In the autosomal dominant inherited forms of FTLD, less than 50% of the patients are due to mutations in known FTLD genes, i.e. C9orf72, MAPT, GRN, VCP and CHMP2B. In approximately 50% of the familial patients the causal gene remains unknown, demanding further investment in genetic and genomic studies of FTLD. The main objective of this project is to identify the missing genes by means of whole genome sequencing in familial FTLD patients. The complete genome sequence of related and unrelated familial FTLD patients are analyzed for the presence of segregating and/or shared sequence variants

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    VIB-European Medical Information Framework (EMIF). 01/01/2013 - 31/12/2017

    Abstract

    Advances in medical research require an increasing quantity and detail of human health data to answer increasingly complex and detailed research questions. At the same time, huge volumes of human health data are being collected and electronically stored, but such data sources are typically fragmented in a variety of environments and systems and often used in isolation. Hence, the full potential of the available human health data is yet to be realized. Additionally, privacy, legal and ethical issues are not always properly covered. The IMI-funded European Medical Information Framework (EMIF) project aims to create an environment that allows for efficient re-use of existing health data. The project includes two specific disease oriented research topics, one of which is Alzheimer's disease (EMIF-AD). The overall aim of EMIF-AD is to build an information framework for studies on neurodegeneration to discover and validate predictive and prognostic AD biomarkers for the facilitation of drug development and trial design in pre-dementia AD. In this setting, we will perform massive parallel amplicon-based sequencing of causal and susceptibility genes on a cohort of 1000 carefully selected European individuals in the prodromal stages of AD (asymptomatic with biomarker signs of AD, subjective cognitive impairment or mild cognitive impairment), and use these data in advanced genetic risk profiling and genotype-phenotype correlation studies, to explore the potential of genetic risk profiling in identification of high risk individuals during an optimal therapeutic window of opportunity. In addition, our genetic data on this cohort will be aligned with other types of –omics data, clinical, neuropsychological, biochemical and neuroimaging markers of disease in an integrated data analysis.

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    VIB-Systems biology of pathways involving brain ageing (AgedBrainSYSBIO). 01/01/2013 - 31/12/2016

    Abstract

    AgedBrainSYSBIO is a 4-year collaborative project funded by the EC under the 7th Framework Programme (FP7), which addresses the basis of brain ageing by studying the pathways through which the ageing phenotype develops in normal and in neurodegenerative conditions. Novel pathways and their evolutionary properties will be modeled and experimentally tested in order to identify druggable targets, eventually providing new diagnostic tools and drug discovery programs that will directly benefit ageing populations. In this context we perform massive parallel resequencing of known and novel risk genes for Alzheimer Disease (AD) in a patient-control design, to identify true susceptibility alleles that may pinpoint alterations of protein-protein interactions. This genetic effort may provide the AgedBrainSYSBIO partners candidates, for mouse and drosophila models, to explore the functional pathways that are involved in pathogenesis of AD. We will use a targeted resequencing approach, based on MASTR and on HaloPlex enrichment technology. Bioinformatics analysis will be performed, followed by statistical analysis of common and rare genetic variants. In addition, we contribute to AgedBrainSYSBIO by providing biomaterials for transcriptomic analysis, and for the induction of pluripotent stem cells to generate patient-derived neurons to model functional pathways and protein interactions in subregions of neurons.

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    VIB-Biomarker based adaptive development in Alzheimer (BioAdaptAD). 01/01/2013 - 31/12/2016

    Abstract

    BioAdaptAD is a Transformational Medical Research consortium project coordinated by Janssen Pharmaceuticals (module 1 (R&D)) and academic partners at the University of Antwerp, the KU Leuven and the VIB (module 2, strategic basic research). The project is focusing on development and implementation of multiple adaptive clinical trials for Alzheimer dementia (AD) and strategic basic research on biomarkers that will enable adaptive trials as decision making tools. Module 2 has an exclusive focus on the pre-dementia stage of mild cognitive impairment (MCI), and will address the question which MCI patients are most likely to convert to AD, i.e. are most likely to show an increase in amyloid deposition, and which in vivo methods are optimally suited to detect or predict this conversion. Defining these methods will enable adaptive clinical trials, and will catalyze the paradigm shift from 'diagnose and treat' to 'predict and prevent' once effective treatments are available. Our contribution specifically aims to identify a set of genetic markers which can predict risk of AD in the MCI phase, to enable intervention early in the natural course of disease. The predictive value of genetic markers will be tested by massive parallel amplicon-based resequencing of selected genes using the MASTR technology in a prospective cohort of MCI patients, including biochemical analyses of CSF and extensive neuroimaging, to study genotype-phenotype correlations. Data will be analyzed with an established bioinformatics and statistical pipelines, and replicated in existing AD and MCI cohorts.

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    Identification of genetic modifiers of onset age in frontotemporal lobar degeneration: a family-based integrative approach. 01/01/2013 - 31/12/2016

    Abstract

    The aim of this PhD project is to identify genetic modifiers underlying the wide variation in onset age in frontotemporal lobar degeneration or FTLD. A quantitative trait locus (QTL) for onset age was identified in an extended Flanders-Belgian FTLD founder pedigree (DR8 family) segregating a causal mutation in the granulin gene. To identify the functional variation underlying the QTL, we apply a multi-omics approach combining whole genome sequencing with brain whole transcriptome and serum whole proteome analysis of members of the DR8 family.

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    The European Early-Onset Dementia consortium. 01/01/2013 - 31/12/2015

    Abstract

    This project finances the coordination activities of the European Early-Onset Dementia (EU EOD) consortium. The EU EOD consortium was founded in 2011 by the P.I. to promote and facilitate translational genetic and clinical research of early-onset dementia (EOD) at the European level. The aim of the consortium is to capitalize on the genetic power of EOD patients combined with the novel –omics technologies that have become available. The consortium consists of 29 partners from 14 EU countries. These are dementia expert centers covering the fields of neurology, neuropathological, clinical research (biomarkers, neuroimaging) and treatment trials, medical genetics and molecular genetics. Amongst the participating centers, collections includes > 5000 EOD patients with an expected yearly growth of 500 patients. The FWO ICA fund supports the coordination and activities of the consortium such as organizing regular meetings between the partners either in conjunction with international conferences or of formal EU EOD consortium annual meetings.

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    Elucidation of the frontotemporal lobar degeneration and amyotrophic lateral sclerosis disease spectrum: genomic characterization of C9orf72 and identification of novel genes. 01/10/2012 - 15/10/2016

    Abstract

    This research project aims at further unraveling and characterizing the genetic etiology of FTLD-ALS to get a better insight into the disease mechanisms underlying the overlap between both disorders. We will achieve this by two different approaches. First, we will genetically, clinically and pathologically characterize the C9orf72 gene and mutation carriers. This includes extensive genotype-phenotype correlations and unraveling of the mechanism by which the C9orf72 repeat expansion occurs and causes disease. Second, we will explore other novel FTLD-ALS genes causing the disease in FTLD-ALS families unexplained by a C9orf72 repeat expansion by genome-wide linkage, whole-genome sequencing and genome-wide search for repeat expansions. As an ultimate goal, these genes can act as new molecular targets for future therapies.

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    VIB-Decoding Alzheimer disease and related disorders. 01/05/2012 - 30/04/2015

    Abstract

    This MetLife Award for Medical Research project is focused human molecular genetics of complex diseases of the central nervous system e.g. Alzheimer disease (AD) and related disorders. The common denominator of these diseases is that they seriously affect the quality of life of adults by affecting their behavior (e.g. memory and cognition) inclusive their personality, emotion and human dignity. Pioneering research in neurodegenerative dementias includes several major contributions e.g. pinpointing the amyloid precursor protein (APP) as a key protein in the Alzheimer disease process and more recently the identification of a major role for the growth factor, progranulin, in frontotemporal lobar neurodegeneration and the identification of the C9orf72 gene that links FTLD and ALS in one disease spectrum. Current AD research is focused on the search for novel causal genes in early-onset families as well as on the identification of genetic risk factors in early-and late-onset patient cohorts including successful collaborations in primary genome-wide association (GWA) studies. The science is still focused on the genetics of neurodegeneration but using novel next generation sequencing technologies to identify both causal genes in early-onset forms of dementia as well as risk genes in late-onset disease. Further functional genomics is used to generate novel mice models for the different proteinopathies. Also there is an ongoing extensive investing in translational research to help understand the biology of the different neurodegenerative processes observed in AD and FTLD and to translate these findings in instruments that support early diagnosis.

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    An integrated approach towards understanding the pathogenesis of neurodegeneration (NEUROBRAINNET). 01/04/2012 - 31/12/2017

    Abstract

    We aim to establish an integrated network to identify genes and proteins involved in neurodegenerative disorders, determine their biological functions, establish their role in the pathophysiological processes, identify modifiers of the function by genetic screens, The network meets the prerequisites for such a project: frontline research in functional genomics related to human health, creating synergies with and between research efforts, teaming up with clinical groups through translational research for providing novel avenues for diagnosis, prevention, treatment and providing training and mobility to improve the skills of our young researchers.

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    VIB-Novel genomic technologies to unravel early-onset Alzheimer etiology. 01/04/2012 - 31/03/2015

    Abstract

    This project represents a formal research agreement between UA and on the other hand USAMRAA. UA provides USAMRAA research results mentioned in the title of the project under the conditions as stipulated in this contract.

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    Institutional funds VIB8 2012-2016: Department of Molecular Genetics. 01/01/2012 - 31/12/2016

    Abstract

    The VIB Department of Molecular Genetics (DMG) is specialized in the genetic analysis of complex neurological and neuropsychiatric diseases. All these diseases are multifactorial in nature i.e. they are expressed due to the interplay of genes and environment. In some of these diseases the inheritance pattern is mainly Mendelian with gene defects in single genes. In others only in a small fraction of patients genetic factors are apparent. In the latter cases, several families with Mendelian inheritance have been identified (= monogenic component). In the majority of the cases the disease expression is modulated by complex gene-gene and gene-environment interactions. Our major aims are to identify novel molecular mechanisms for disease causation and effective drug treatment for these devastating diseases. We use different genetic and genomic approaches to identify genes (causal mutations) and genetic risk factors (predisposing polymorphisms) based on molecular genetics, genetic epidemiology and functional genomics approaches. The contribution of a disease gene is estimated in population and hospital based patient series. Also, we will examine these genes and risk factors in relation to other genes as well as to environmental risk factors. To understand the pathogenic role of these mutations and polymorphisms, we will use cellular systems, mouse and Drosophila models. Also, the observed biological phenomena can be compared directly with those observed in patients. Finally, these models should allow us to test for treatment approaches. There are currently 5 research groups within the department that are each headed by a faculty member: Neurodegenerative Brain Diseases (Christine Van Broeckhoven PhD DSc), Neurogenetics (Peter De Jonghe MD PhD), Peripheral Neuropathies (Vincent Timmerman PhD), Molecular Neurogenomics (Albena Jordanova PhD) and Applied Molecular Genomics (Jurgen Del-Favero PhD).

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    Identification of novel LBD genes using genomic sequencing technology. 01/01/2012 - 31/12/2015

    Abstract

    Lewy body disorders are common brain diseases that cause extensive disability and reduction of the quality of life. Parkinson disease and Dementia with Lewy bodies are diverse manifestations of this disease spectrum and show substantial clinical overlap suggesting that these diseases may be caused by overlapping disease processes. Without the development of early diagnostic tools and therapies that allow intervention at a non-incapacitating stage of the disease, Lewy body disorders will confer a major socio-economic problem in our society. Therefore, we require a profound knowledge of the underlying biological processes and a subsequent efficient translation of new insights into improved patient care. With this research project we aim to unravel underlying causes and disease mechanisms of Lewy body disorders, in particular through the identification of novel causal genes for familial Lewy body disorders. We will profit from state-of-the-art technologies to speed up the identification of novel genes and to investigate their role in Lewy body disorders and related brain diseases. We also aim to asses the biological effect of the identified gene defects to generate novel insights in the disease processes which will eventually lead to improved therapeutics and more accurate diagnostic tools.

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    Genetic risk factors for Alzheimers's disease: a search for pathomechanisms. 01/01/2012 - 31/12/2015

    Abstract

    Alzheimer's disease (AD) is the most common form of dementia. By pooling many study populations and thus increasing statistical power, recent international genome wide association studies have uncovered 10 novel genes associated with Alzheimer's risk (CLU, CR1, PICALM, BIN1, ABCA7, CD2AP, CD33, EPHA1, MS4A4E and MS4A6A). The principal aim of this project is to identify and extensively investigate novel genetic risk variants that might explain pieces of the missing heritability of AD. We will use next-generation sequencing technology to investigate the entire novel AD genes, including up- and downstream regulatory regions, in our prospective Flanders-Belgian study population (currently 1263AD patients and 1029 control individuals). The genetic follow-up of these AD genes consists of 5 tiers: Identification of a common genetic variant that explains the observed association between the gene and AD, in a high-density SNP-based analysis of the Flanders-Belgian AD study population. Exploration of the presence of both rare variants and structural variations in the novel AD genes. We will also investigate the possibility of genetic interactions between different genes because of the complexity of late onset AD. Further we will perform genotype-phenotype correlation studies with phenotypes ranging from biomarker profiles in CSF, plasma or serum to clinical phenotypes. Lastly we will investigate the functional effect of the associated variations.

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    VIB-Integrated approach to identify novel genes for frontotemporal lobar degeneration (CoEN). 01/01/2012 - 31/12/2013

    Abstract

    Frontotemporal lobar degeneration (FTLD) is an umbrella term for degenerative diseases of the frontal and temporal brain lobes. FTLD is a type of dementia clinically characterized by behavioural and language disturbances and mainly affects people between 40 and 60 years of age, strongly involved in career and social activities. In about 50% of cases FTLD is familial, mostly with autosomal dominant inheritance. About 20% of familial FTLD is explained by disease genes known today. The neurobiology of FTLD is poorly understood and preventive or curative therapy is unavailable. This network will bring together world experts in molecular genetics and cell biology of FTLD to identify novel disease genes and to generate animal models as well as novel tissue culture models (induced neurons) to functionally study disease initiation and propagation. This will result in a better understanding of the biological pathways involved in FTLD, improved diagnostics and the identification and development of targeted therapeutic approaches.

    Researcher(s)

    Research team(s)

    Translational research of pathomechanisms for frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). 01/01/2012 - 31/12/2013

    Abstract

    TAR DNA-binding protein 43 (TDP-43) was recently shown to be the main protein component of ubiquitinated inclusions found in patients with frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), diseases that constitute the spectrum of primary TDP-43 proteinopathies. Over the last years, our research group has been successful in the generation of different mouse models modeling TDP-43 proteinopathies of the FTLD-ALS spectrum, including progranulin knock-out (Grn-/-) and human TDP-43 (hTDP-43) overexpression mice. We are aiming to redirect our research focus from the basic characterization of FTLD/ALS mouse models towards patient-directed translational research. Hereto, we are establishing different stable neuronal and glial cell lines derived from the Grn-/- mouse model to gain more insights in the aetiology of FTLD-TDP and ALS pathology. Furthermore, to accelerate translation of genetic findings into biological relevant insights, we will set up a procedure for the generation of induced pluripotent stem (iPS) cells from a series of selected FTLD/ALS patients that carry known mutations associated with TDP-43 proteinopathy. The strength of these approaches is that it allows studying the effect of the disease protein on the relevant cell types that degenerate during the disease process. These cells will be characterized biochemically to illustrate whether they can reproduce the features of TDP-43 proteinopathy and serve as a powerful disease model.

    Researcher(s)

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    Molecular genetics and biomarker research of frontotemporal lobar degeneration supported by robust biosampling and biobanking strategies. 01/10/2011 - 30/09/2014

    Abstract

    In the past decade remarkable advances have been made in understanding the origin of frontotemporal lobar degeneration (FTLD), after Alzheimer's disease one of the leading causes of dementia. In sharp contrast however, is the absence of any therapeutic strategy based on these novel discoveries and the fact that a significant portion of patients remains in which the source of the disease is still unknown. This research project proposes an integrated approach to further uncover the genetic etiology of FTLD. This includes the establishment of a centralized repository of tissues and biofluids from medically and molecularly thoroughly characterized, extended collections of FTLD patients and unaffected individuals (biobank). This powerful biobank will allow the set-up of state of the art genetic studies of FTLD. We will participate to international large scale genome-wide association studies aiming to discover genetic risk factors for FTLD. We will further investigate these findings in our population of Flanders- Belgian FTLD patients to examine population-specific risk profiles. Moreover, the biobank will facilitate translation of knowledge obtained from these basic molecular research studies into clinical applications for improved diagnosis and treatment of future patients.

    Researcher(s)

    Research team(s)

    An integrated genetic and functional approach towards understanding the complex etiology of Alzheimer's disease. 01/10/2011 - 30/09/2014

    Abstract

    Alzheimer's disease (AD) is the most common form of dementia worldwide. Whereas molecular genetic research has been successful in the dissection of the etiology of early-onset autosomal dominant forms of AD, so far only part of the multifactorial etiology of the majority of AD patients is explained. Given the large socioeconomic impact of Alzheimer's disease, it is of paramount importance to design efficient strategies for the delineation of the genetic predisposition of this devastating neurodegenerative disease. The main objective of this project is to come to a fuller understanding of the genetic underpinnings of the complex form of AD. A high-throughput genome-wide association (GWA) study on our complete Belgian-Flanders study population will detect novel risk factors that will be further studied into detail by exploring all types of genetic variants and their possible in silico effects on disease. Secondly, the pathogenic character of recently identified CLU variants and novel variants of interest will be functionally characterized by means of suitable in vitro systems. These studies will provide important insights into disease mechanisms, and clues towards risk prediction profiling of patients and the development of earlier diagnoses and more targeted therapies in the future.

    Researcher(s)

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    Detection of novel genes for frontotemporal lobar degeneration using whole-genome sequencing. 01/10/2011 - 30/09/2013

    Abstract

    Worldwide, almost 35.6 million people are suffering from dementia, accounting for 3.4% of all deaths in high-income countries. The possibilities for prevention and treatment of dementia are limited and the risk of developing the condition rises steeply with age resulting in an increasing number of patients suffering from this disease. Global population ageing will result in huge increases in the number of patients with dementia, which is estimated to double every 20 years. In Belgium alone, around 163 500 are suffering from dementia. My PhD project is mainly focusing on frontotemporal lobar degeneration (FTLD), which is, after Alzheimer disease, the most common cause of dementia in patients younger than 65 years. FTLD is a clinically heterogeneous group of conditions caused by neuronal degeneration of the frontal and temporal lobes of the brain. Main clinical characteristics include changes in personality and behavior, impairment of language, and executive dysfunction. About 50% of the FTLD patients show familial history of dementia, suggesting that genetic predisposition plays a major role in the etiology of FTLD. In the autosomal dominant inherited forms of FTLD, less than 50% of the patients are due to mutations in known FTLD genes, i.e. C9orf72, MAPT, GRN, VCP and CHMP2B. In approximately 50% of the familial patients the causal gene remains unknown, demanding further investment in genetic and genomic studies of FTLD. The main objective of this project is to identify the missing genes by means of whole genome sequencing in familial FTLD patients. The complete genome sequence of related and unrelated familial FTLD patients are analyzed for the presence of segregating and/or shared sequence variants.

    Researcher(s)

    Research team(s)

    Clinical and genetic epidemiology of Parkinson's disease: focus on disease progression and non-motor symptoms. 01/10/2011 - 30/09/2012

    Abstract

    Parkinson's disease (PD) is the second most common neurodegenerative brain disorder. Five causal genes (SNCA, LRRK2, PARK2, PINK1 and DJ1) leading to familial PD have already been identified. Variations in these genes have also been shown to increase susceptibility for sporadic PD. In my project, I am prospectively recruiting a population of familial and sporadic PD patients. Detailed phenotypic characterization of the patients is performed with standardized clinical scales at different time intervals. Genetic variations (simple and complex mutations) in the known causal genes will be identified and genotype-phenotype correlations will be established. Since disease progression is an important part of the phenotypic variability of PD, these correlations will focus on clinical features associated with disease progression, non-motor symptoms and motor complications. Genetic association studies will be conducted to identify new genetic risk factors for PD. In informative families new causal PD genes will be identified using a positional cloning strategy. The combination of objective and longitudinal clinical data on disease progression in a genetically well-characterized population of PD patients, is a major asset of the project.

    Researcher(s)

    Research team(s)

    Prize CBC Banque: Progranulin in neurodegenerative dementia: genetic, functional and neuropathological characterization. 16/06/2011 - 31/12/2011

    Abstract

    Frontal temporal lobar degeneration (FTD) is the second most common cause of dementia in people younger than 65 years. Molecular genetic research has successfully identified a number of causal genes. One important disease gene codes for granulin a protein with growth factor activities.The loss of 50% of granulin causes inherited autosomal dominant FTD. The biological mechanism how this happens is still largely unknown. Hereto, extensive functional research is nodded in the laboratory and in experimental animals.

    Researcher(s)

    Research team(s)

    Molecular genetics of early-onset Alzheimer's disease. 01/01/2011 - 31/12/2014

    Abstract

    Early-onset Alzheimer's disease (AD) is a fatal neurodegenerative dementia occurring in mid-life (onset of disease between 30 and 65 years) that is severely disruptive for patients and their relatives. An estimated 3000 to 11000 people have early-onset AD in Belgium. Early-onset AD has a strong genetic component, but the majority of the genetic etiology is still unresolved, as mutations in the known dementia genes and the genetic risk conferred by APOE ε4 do not explain more than 10-20% of the occurrence of early-onset AD. The aim of this project is to further unravel the genetic etiology of early-onset AD beyond pathogenic mutations in the known dementia genes by combining a well-documented homogeneous study population with the newest technologies in molecular genetics, to come to a fuller understanding of the pathogenesis of AD. We will employ family-based studies to identify novel pathogenic mutations and rare variants, and we will perform population based whole genome studies to identify potential recessive causes of disease, as well as common genetic risk factors, rare variants and modifying factors. Promising genetic variants will be followed up by functional characterization, genotype-phenotype correlation studies and translation into biomarkers.

    Researcher(s)

    Research team(s)

    Identification and characterization of novel causal genes for Lewy Body disorders using next-generation sequencing. 01/01/2011 - 31/12/2014

    Abstract

    Lewy body disorders (LBD) represent a heterogenic group of neurodegenerative brain diseases (NBD) characterized by the presence of intraneuronal α-synuclein containing inclusions, called Lewy bodies. The Lewy body variant of Alzheimer's disease marks one end of the spectrum, Parkinson's disease (PD) the other and Lewy body dementia and Parkinson with dementia are both located in-between. PD is the second most common NBD, affecting ~2 % of the population older than 65 years and causing major disability and reduction of the quality of life. Genetic linkage studies in rare families with autosomal dominant or recessive inheritance of PD identified at least five genes in which mutations lead to PD. The study of the corresponding gene products was the primary source of the current knowledge on PD pathogenesis. However, the contribution of these genes to the genetic etiology of PD in the Belgian population is relatively limited. The main aim of this PhD project is to contribute to the identification of novel causal PD genes using whole genome sequencing in Belgian families segregating PD. Furthermore, we aim at characterizing the pathogenic effect of the identified disease associated genetic variants using 'state of the art' functional genomics/genetics approaches. The expected results are thought to further elucidate the pathomechanisms underlying PD and related LBD and will pave the way for the development of more accurate diagnostic tools and effective drugs/therapies.

    Researcher(s)

    Research team(s)

    Molecular genetic research into the complex genetics of frontotemporal lobar dementia. 01/01/2011 - 31/12/2012

    Abstract

    Frontotemporal lobar degeneration (FTLD) is a form of dementia characterized by progressive alternation of personality and/or language problems. In up to 50% of FTLD patients a family history of the disease is observed indicating an important role of genetic factors to the development of the disease. Causal mutations are found in the PGRN, MAPT, VCP and CHMP2B genes, which explain now 10 to 20% of FTLD patients. In this project I seek to identify novel genetic factors that contribute to the risk of developing FTLD. To this end, genome-wide association studies will be conducted which allow screening of the complete genome in high density and in an unbiased manner for association between genetic variants and disease. When large families with Mendelian segregation of the disease are collected, genetic linkage analysis will be performed to identify novel causal genes for FTLD. Newly identified genetic factors will be evaluated whether they are correlated to clinical subtypes, specific abnormalities on neurological imaging, protein profiles in serum and plasma and neuropathological findings. Fur these purposes I will invest in assembling a large study population of FTLD patients, which will be clinically, genetically and pathologically characterized in detail and of whom different sources of biological material will be collected ¿ DNA, cell-lines, serum, plasma and brain.

    Researcher(s)

    Research team(s)

    Project website

    Elucidation of the role of progranulin in frontotemporal dementia. 01/10/2010 - 30/09/2012

    Abstract

    Progranulin (GRN) is a multifunctional secreted growth factor expressed in a wide variety of tissues including the central nervous system (CNS). GRN is involved in various important cellular functions including cell cycle progression, cell motility, wound repair and inflammation and loss of GRN is associated with frontotemporal dementia (FTD). The precise mechanisms underlying GRN-mediated cell proliferation and neuronal survival as well as a link with TDP-43, that is cleaved, phosphorylated and deposited as intraneuronal inclusions in FTD patients, are not yet well understood. In the first part of this project we showed that loss of Grn in mixed cortical cultures led to increased caspase activation and decreased TDP-43 solubility. In the next term we will investigate the precise cell types responsible for the observed GRN-dependent phenotype. We will therefore study whether this neurodegenerative phenotype is caused by an intrinsic defect of the neurons, a defect of glial cells (e.g. astrocytes), which can not support the survival of neurons, or a combination of both. Therefore we aim to establish conditional astrocyte-specific Grn knockout mice as well as primary glial cultures from Grn-/- and wild-type mice which will then be analyzed for signs of increased cellular stress or degeneration like caspase-3/7 activity, TUNEL staining, expression of cell stress molecules etc.. The biochemical properties of TDP-43 in astrocytes such as sub-cellular localization, processing and any pathological alterations due to Grn loss, like increased TDP-43 phosphorylation, insolubility, fragmentation and "nuclear clearing", will be investigated by both immoncytochemistry and immunoblotting techniques. Co-cultures of primary wild-type neurons on astrocyte feeder layers of Grn-/- or wild-type mice will be used to study alterations in neuronal differentiation, polarization and increased signs of degeneration like decreased levels of synaptic proteins on immunocytochemistry, decreased neuritic growth/axonal length by fiber tracking experiments, and morphological appearance of de-differentiation. Furthermore co-cultures experiments will be used to investigate any reduced capacity of Grn-/- astrocytes to protect neurons from neurotoxicity. Continued characterization of the described cellular models would provide us important insights in the underlined mechanisms by which Grn haploinsufficiency causes decreased neuronal survival.

    Researcher(s)

    Research team(s)

    The Biomark Microfluidics system for high throughput genotyping, expression profiling and CNV analysis. 22/07/2010 - 30/09/2013

    Abstract

    The microfluidic BioMark¿ Genetic Analysis Platform from Fluidigm (www.fluidigm.com) is a fully integrated system enabling high throughput analysis of gene expression, SNP genotyping and absolute quantification of nucleic-acid sequences utilizing Digital and/or Dynamic Array Integrated Fluidic Chip (IFC) technology. Besides increasing the genetic and genomic analysis capacity the system at the same time enables significant reduction in the use of precious DNA/RNA samples and significant reduction (up to 100-fold) of consumable cost due to the nanoliter based reaction volumes (i.e. cost per datapoint).

    Researcher(s)

    Research team(s)

      Molecular epidemiological approaches in a translational study of complex Alzheimer dementia. 01/01/2010 - 31/12/2013

      Abstract

      Alzheimer dementia (AD) is a common, incurable disorder. Because of changing demographics, the prevalence of AD increases rapidly. This project aims to advance understanding of the genetic etiology of AD, amongst others in explorative association studies of genes in their biological networks, and ultra-high throughput sequencing to characterize allelic heterogeneity. In addition to AD we will also study the phenotype mild cognitive impairment to detect genetic factors that play a role early in the pathological cascade. In addition we propose an integrated approach of genetics and proteomics. By performing these analyses on the same individuals, we can examine if 'prognostic' genes can also affect easily measurable quantitative biomarkers such as differences in protein expression.

      Researcher(s)

      Research team(s)

      Characterizing genes and molecular mechanisms involved in frontotemporal lobar degeneration (FTLD) using an integrated approach of molecular genetics and functional genomics. 01/01/2010 - 31/12/2013

      Abstract

      In this project, we will apply an integrated approach of molecular genetic and functional genomic strategies to identify novel genes causing FTLD, modifying one's risk to develop FTLD, and/or altering clinical expression of the disease. Further, we will identify functional pathways and cellular processes that are affected in FTLD. Studies of the function and dysfunction of FTLD genes and pathways will greatly expand our knowledge of neurodegenerative disease mechanisms.

      Researcher(s)

      Research team(s)

      Mechanism of dense plaques formation in Alzheimer's disease. 01/01/2010 - 31/12/2011

      Abstract

      Amyloid-ß (Aß) aggregation in brain parenchyma as amyloid plaques is a neuropathological hallmark of Alzheimer's disease (AD). Interestingly, only dense-core plaques are associated with neuritic and inflammatory pathology in AD patients as well as in mouse AD models. However, the precise neuropathological changes that occur in brain in response to amyloid deposition are largely unknown. Several lines of evidence suggest that Aß does not aggregate spontaneously in brain but is rather assisted by specific chaperones that help Aß to aggregate into ß-sheets. Utilizing transcriptomic and proteomic analysis, the project aims to elucidate the mechanism(s) of dense-core plaque formation in various plaque-depositing transgenic mouse AD models. Interestingly, we have shown in an unbiased transcriptomic analysis that progranulin is upregulated in microglia, neurons and neurites in association with dense-core plaques in brains of Tg2576 and APPPS1 mice, as has also been shown for AD patients, which prompts for testing progranulin as a biomarker for human studies. To further investigate the role of progranulin in AD pathogenesis, we have crossed APPPS1 mice with progranulin overexpression and progranulin knock-out mice. These studies would aid in developing novel potential therapeutic strategies for preventing or treating Alzheimer's disease.

      Researcher(s)

      Research team(s)

      Identification and characterization of new causal genes and risk factors for 'Lewy body' brain diseases. 01/01/2010 - 31/12/2011

      Abstract

      Lewy body diseases (LBD) represent a clinicopathological spectrum of disorders ranging from Alzheimer disease (AD) over Lewy body dementia (DLB) to Parkinson disease (PD). Despite the relatively high combined prevalence of LBD, the genetic etiology of these neurodegenerative brain diseases remains to be further elucidated. Unraveling the genetic components of complex human diseases is one of the main challenges in the field of modern human genetics. With this research project we aim to significantly contribute to the dissection of LB associated neurodegeneration by using a combination of state-of-the-art molecular genetic and functional genomic approaches. The identification of novel causal genes (family-based) and genetic risk factors (population-based), as well as the exploration of the mutation spectrum of known LBD associated genes in combination with detailed clinical and functional phenotyping, will lead to a better understanding of the molecular genetic etiology of LBD. Moreover, the identification of the underlying causes of LBD will pave the way for subsequent development of effective cures and/or preventive measures.

      Researcher(s)

      Research team(s)

      Characterization of new mouse models for frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). 01/01/2010 - 31/12/2011

      Abstract

      Recently, ubiquitinated and N-terminally truncated forms of TAR DNA binding protein (TDP-43) were also identified as a major protein constituent of nuclear and cytoplasmic inclusions in patients of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Almost all TDP-43 mutations have been identified in patients with sporadic and familial forms of ALS. Besides, mutations in the valosin-containing protein (VCP) and progranulin gene have also been identified to cause FTLD with a burden of TDP-43 positive inclusions. Our research group has established a number of transgenic mouse models for these genes to study the underlying mechanisms which can lead to neurodegeneration or TDP-43 accumulation in these patients. The specific aims of this project are the characterization of human mutant TDP-43 (M337V) and human mutant VCP (R159H) overexpression mice as a potential FTLD and/or ALS model. These mice will be analyzed behaviorally, biochemically and neuropathologically to illustrate whether they have more severe neuronal loss in the cortical and/or spinal motor neurons and develop gait abnormalities, cognitive or other behavioral defects, which are more severe than those observed for wt hTDP-43 or wt-hVCP mice respectively. Lastly, a crossbred progranulin knock-out (Grn-/-) x wt-hTDP-43 overexpressing mouse model will be generated to investigate the relevance of Grn loss on a humanized TDP43 background. These mouse models could serve as important disease models for FTLD or ALS.

      Researcher(s)

      Research team(s)

      Molecular genomics of TDP-43 positive frontotemporal lobar degeneration (FTLD-TDP): elucidation of disease pathways through an integrated approach. 01/10/2009 - 30/09/2012

      Abstract

      Frontotemporal lobar degeneration (FTLD) is a severe neurodegenerative brain disease with a prevalence similar to that of Alzheimer's disease (AD) in patients with an early onset of disease. However, an appropriate therapy is not yet available. Clinical FTLD characteristics are often accompanied by amyotrophic lateral sclerosis (ALS) symptoms. Pathologically, most patients show TDP-43-positive brain inclusions (FTLD-TDP). Genetic factors play an essential role in the etiology of the disease since mutations were identified in several key genes MAPT, GRN, VCP and CHMP2B and linkage was found with a locus on chromosome 9p13-p21 in several FTLD-ALS families worldwide. FTLD-TDP neuropathology was described in GRN and VCP mutation carriers and in 9p13-p21 linked families. Therefore, these genes are probably involved in common disease mechanisms. Furthermore, not in all patients with TDP-43 brain deposits the disease is explained by mutations in one of the known genes indicating that still other genes have to be involved in the pathway(s) leading to TDP-43 pathology. In this project we will perform transcriptome analyses and in silico co-expression studies and interactome analyses to identify interaction partners of the known FTLD-TDP genes/proteins GRN, VCP and TARDBP (TDP-43) with a possible function in biological pathways leading to FTLD-TDP pathology. The genes encoding these interaction partners will be implemented in molecular genetic analysis to identify genetic variants contributing to the genetic etiology of FTLD. This will also lead to the detection of biological processes probably involved in the disease. More specifically we will search for a new FTLD-TDP gene in an FTLD-ALS family with FTLD-TDP pathology, linked with the known FTLD-ALS locus on chromosome 9p, using genomic approaches. The underlying gene will most likely explain a significant part of FTLD etiology. With this research we will further unravel the complex genetic heterogeneity of FTLD and better understand the link between mutations in the FTLD-TDP genes and TDP-43 pathology. This will significantly contribute to the understanding of the pathways involved in FTLD and related neurodegenerative diseases including ALS, AD and Parkinson's disease, and to the identification of new therapeutic targets leading to relevant therapies halting or preventing the disease.

      Researcher(s)

      Research team(s)

      Functional genomics of Alzheimer disease: Characterization of the risk effect of progranulin missense mutations. 01/10/2009 - 30/09/2012

      Abstract

      The general aim of this project is to investigate the functional effect of genetic variants, identified through molecular genetic research, that are associated with an increased risk for AD or FTLD. More specifically we aim to elucidate the functional effect of GRN missense mutations. To this end we will use both in vitro (cellular) and in vivo (mice) model systems.

      Researcher(s)

      Research team(s)

      An integrated approach of genetic epidemiology and molecular genetics in the study of Alzheimer dementia and related phenotypes. 01/10/2009 - 31/12/2011

      Abstract

      This project aims to contribute to a better understanding of the genetic etiology of complex forms of Alzheimer dementia by means of genetic-epidemiological and molecular genetic techniques. This will help in identifying molecular mechanisms that can serve as targets for early detection, prevention and treatment of this common and incurable disease. High-throughput association studies (both genome-wide and focused on biological pathways) and intermediary or endophenotypes will be performed in a well-characterized study population with sufficient statistical power. Translation of findings to prodromal stages of AD will point out which factors are already of relevance early in the pathological cascade. These factors might find use as early predictors. Pathway analysis will identify subgroups with an increased epidemiological risk profile. In addition, we will assess if these prognostic markers affect easily measurable quantitative traits, e.g. in an integrated study of genome wide genotype data and differential protein expression in a proteomics study. If a correlation can be demonstrated, this trait can be used as a biomarker specific to the disease process. In addition we aim to identify genetic factors that modify onset age, to find novel targets for treatment, to delay or prevent the pathological cascade.

      Researcher(s)

      Research team(s)

      Molecular genetic analysis of Alzheimer dementia. 01/10/2009 - 30/09/2011

      Abstract

      Alzheimer's disease (AD) is the most common form of dementia in the elderly. In the majority of AD patients the molecular cause of neurodegeneration is so far unknown. Once AD appears it can be considered as an end point of several disease processes which impedes the research of the exact etiology. Intermediate phenotypes such as the episodic memory, which change early in the pathological process are more directly under influence of the underlying genetic factors and can therefore support the genetic research of AD. By a molecular genetic approach this project will contribute to the research of the neurodegenerative process in AD and will therefore lead to a better understanding of the etiology of dementia. Genetic association studies on selected candidate genes as well as genomic association studies will be performed in a large and well characterized Belgian AD population. The role of the identified AD risk genes in the conversion of "Mild Cognitive Impairment (MCI)" to AD will be further investigated in MCI patients. Results from the AD research will also be analyzed in a group of healthy individuals coming from a Swedish memory population. Additionally we will identify novel biomarkers in plasma or cerebrospinal fluid using amyloid beta quantifications and proteomics profiling experiments. When genetic informative multiplex families are available, genomic linkage studies will be carried out.

      Researcher(s)

      Research team(s)

      Clinical and genetic epidemiology of Parkinson's disease: focus on disease progression and non-motor symptoms. 01/10/2009 - 30/09/2011

      Abstract

      Parkinson's disease (PD) is the second most common neurodegenerative brain disorder. Five causal genes (SNCA, LRRK2, PARK2, PINK1 and DJ1) leading to familial PD have already been identified. Variations in these genes have also been shown to increase susceptibility for sporadic PD. In my project, I am prospectively recruiting a population of familial and sporadic PD patients. Detailed phenotypic characterization of the patients is performed with standardized clinical scales at different time intervals. Genetic variations (simple and complex mutations) in the known causal genes will be identified and genotype-phenotype correlations will be established. Since disease progression is an important part of the phenotypic variability of PD, these correlations will focus on clinical features associated with disease progression, non-motor symptoms and motor complications. Genetic association studies will be conducted to identify new genetic risk factors for PD. In informative families new causal PD genes will be identified using a positional cloning strategy. The combination of objective and longitudinal clinical data on disease progression in a genetically well-characterized population of PD patients, is a major asset of the project.

      Researcher(s)

      Research team(s)

      Integrated platform for target identification, validation and drug discovery with applications for neurodegenerative diseases (Neuro-TARGET). 01/01/2009 - 31/12/2012

      Abstract

      The general aim of this project is to set up an integrated platform for target identification, validation and drug discovery that will lead to novel therapies for neurodegenerative diseases. Therefore, we have assembled an interdisciplinary consortium with complementary expertise and cutting-edge technologies. Our aim is to develop and apply different model systems to identify and validate key molecular events and targets that define the onset of pathology and constitute prime markers for early diagnosis. Validated targets and new assays will foster a drug discovery platform.

      Researcher(s)

      Research team(s)

      Project website

      Molecular genetic research into the complex genetics of frontotemporal lobar dementia. 01/01/2009 - 31/12/2010

      Abstract

      Frontotemporal lobar degeneration (FTLD) is a form of dementia characterized by progressive alternation of personality and/or language problems. In up to 50% of FTLD patients a family history of the disease is observed indicating an important role of genetic factors to the development of the disease. Causal mutations are found in the PGRN, MAPT, VCP and CHMP2B genes, which explain now 10 to 20% of FTLD patients. In this project I seek to identify novel genetic factors that contribute to the risk of developing FTLD. To this end, genome-wide association studies will be conducted which allow screening of the complete genome in high density and in an unbiased manner for association between genetic variants and disease. When large families with Mendelian segregation of the disease are collected, genetic linkage analysis will be performed to identify novel causal genes for FTLD. Newly identified genetic factors will be evaluated whether they are correlated to clinical subtypes, specific abnormalities on neurological imaging, protein profiles in serum and plasma and neuropathological findings. Fur these purposes I will invest in assembling a large study population of FTLD patients, which will be clinically, genetically and pathologically characterized in detail and of whom different sources of biological material will be collected ¿ DNA, cell-lines, serum, plasma and brain.

      Researcher(s)

      Research team(s)

      Project website

      Integrative molecular approach to unravel the etiology of Lewy body brain disorders. 01/10/2008 - 30/09/2011

      Abstract

      Early differential diagnosis in LBD patients is extremely important for prognosis and therapy. We aim to contribute to the elucidation of underlying mechanisms of these disorders using molecular genetic analyses of phenotypically well-characterized patients. The identification of novel genes and risk factors, dissection of the mutation spectrum of known genes combined with detailed clinical and functional phentoyping will lead to a better understanding of the molecular etiology of PD and related disorders. Based on the importance of gene dosage and expression of known PD genes in the pathogenesis of both familial as well as sporadic PD, we will focus particularly on the detection of of copy number variants and other regulatory variations affecting the etiology of LBD due to intracellular changes in the concentration of functional protein. The identification of the underlying causes of these diseases will pave the way for the subsequent development of effective cures and/or preventive measures.

      Researcher(s)

      Research team(s)

      Genetic risk for frontotemporal lobar degeneration: A genome-wide approach. 01/10/2008 - 30/09/2011

      Abstract

      Aging of the global population has caused dementia to become one of the leading causes of morbidity and mortality. Notwithstanding there is still no therapy available that can cure or prevent dementia. For this research project our focus is on frontotemporal lobar degeneration (FTLD). FTLD is after Alzheimer's disease one of the major causes of dementia, accounting for 5 to 10% of all dementia patients and up to 20% of patients younger than 65 years. Up to up to 40% of FTLD patients have a positive family history of dementia. In the last few years major progress has been made in dissecting the genetic etiology of FTLD. Four genes have already been identified for autosomal dominant FTLD ¿ MAPT, PGRN, CHMP2B, VCP ¿ explaining about 20% of patients. Despite these efforts the majority of FTLD patients still remain unexplained. It is expected that in these patients the cause of the disease is complex in nature, i.e. the result of interplay between genetic and environmental factors. The aim of this research project is to identify such genetic factors that contribute to the risk of developing FTLD in a significant fraction of patients trough a genome-wide association approach. To this extent we will invest in the assembly of an extended, well-documented collection of biomaterials ¿ DNA/RNA, plasma/serum, EBV cell lines, fibroblasts, CSF, brain material ¿ from FTLD patients, families, and control individuals to create a powerful tool to undertake genome-wide association studies. This project will allow extended clinical, pathological, and biologic information to be combined with whole-genome information which will in turn offer the potential to increase our understanding of the pathogenesis of FTLD and provide targets for early diagnosis, prevention and therapy.

      Researcher(s)

      Research team(s)

      Elucidation of the role of progranulin in frontotemporal dementia. 01/10/2008 - 30/09/2010

      Abstract

      Progranulin (GRN) is a growth factor involved in tumorogenesis, while loss of GRN leads to frontotemporal dementia (FTD). The precise mechanisms underlying GRN-mediated cell proliferation and neuronal survival as well as a link with TDP43, that is cleaved, phosphorylated and deposited as intraneuronal inclusions in FTD patients, are not well understood. The project aims at developing GRN and TDP43 overexpression and deficient cellular models including primary neuronal cells derived from Grn-/- mice to study the biochemistry and interaction of GRN and TDP43 in disease context. These models will be established using siRNA mediated protein knockdown and expression of tagged/untagged GRN and TDP43 proteins. We will study GRN-mediated cell proliferation as well as other phenotypes using cellular assays such as BrdU proliferation, flow cytometry and caspase-luminescence assays. The established models will also be utilized to study subcellular localization, protein trafficking and turnover of endogenous and/or overexpressed GRN and TDP43 as well as altered signaling pathways. Furthermore the link between GRN deficiency and TDP43 phosphorylation, fragmentation and accumulation will be elucidated in these cell models. Characterization of these cellular models would give us important insights in the mechanisms by which GRN haploinsufficiency causes decreased neuronal survival.

      Researcher(s)

      Research team(s)

      An integrated approach towards understanding the pathogenesis of CNS and PNS disorders. 01/01/2008 - 31/12/2014

      Abstract

      The research activity in the research excellence centre NEURO focuses on molecular genetics and clinical neurology of neurodegenerative diseases comprising diseases of the central nervous system such as Alzheimer disease, Parkinson disease, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis and related diseases; and of the peripheral nervous system such as motor- and/or sensory neuropathies and related disorders. The centre brings together basic and clinical researchers from the Department of Molecular Genetics, VIB, and the Institute Born Bunge, representing two major neuroresearch activities at the University of Antwerp. The general aim of the excellence centre aims at clarifying a series of fundamental questions related to the pathophysiological processes underlying neurodegenerative diseases. More specifically, the elucidation of biological disease pathways by identifying novel genes and genetic risk factors and modifiers of genetic function, by analysing the functional networks in which proteins encoded by these genes are operating, and ultimately, by providing novel avenues for early diagnosis, prognosis, prevention and treatment.

      Researcher(s)

      Research team(s)

      Identification of genes and genetic risk factors for Parkinson's disease. 01/01/2008 - 31/12/2011

      Abstract

      Parkinson's disease (PD) is a complex brain disease and a major player in the spectrum of 'Lewy body' neurodegenerations. Genetic linkage studies in rare PD families identified at least five genes in which mutations lead to PD. The contribution of these genes to the etiology of PD is small but the impact of the functional studies of their gene products and PD related gene defects on the current knowledge of the molecular pathology of PD however is considerable. Thus, the identification and characterization of new genes is essential to further unravel the underlying disease mechanisms of PD and related disorders. Further, correlation studies between the mutation spectrum and clinical phenotypes supports more accurate diagnostics. We also develop cellular assays to quickly and efficiently assess the pathogenicity of mutations, we verify disease related differences in protein- and RNA- expression in patients and further investigate the relation between the protein and PD lesions using immunohistochemistry. Most patients have a sporadic form of PD that most likely originates from a combination of several genetic and environmental factors. To identify risk factors we perform genetic association analyses in well documented groups of patients and control individuals. Because of the importance of gene dosage and expression of known PD genes we focus on variations that lead to intracellular changes in the concentration of the functional protein.

      Researcher(s)

      Research team(s)

      Progranulin in neurodegenerative dementia: genetic, functional and neuropathological characterization. 01/01/2008 - 31/12/2010

      Abstract

      The project aims to employ molecular genetic and pathological studies to further understand the role of progranulin (PGRN) in dementia, and to elucidate the role of modifier genes in the clinicopathological expression of PGRN mutations. These studies will allow designing an optimized protocol for molecular genetic diagnostics. Further, genes modifying disease onset and progression are likely to be effective targets for therapeutic interventions e.g. aiming at disease delay. Furthermore, this project also aims to build mouse and cellular PGRN knockout models - PGRN -/+ and PGRN -/- knockout mice, derived PGRN -/- primary rodent neurons, and siRNA treated immortalized cells - that would serve to elucidate whether and how PGRN loss leads to decreased cell survival and more specifically of the cortical neurons. The cellular models would allow elucidating PGRN cellular trafficking and catabolism as well as the underlying cell signaling pathways that are down regulated in PGRN deficiency. The specific aims of the project are: to evaluate the occurrence of complex PGRN null-mutations in a collection of 190 Belgian FTLD patients as well as study the contribution of PGRN mutations in FTLD-associated neurodegenerative diseases including PD, ALS and AD, to identify genes modifying the highly variable onset age of FTDU associated with PGRN mutations, to construct PGRN knockout mice and illustrate whether PGRN -/+ and PGRN -/- mice have neuronal loss especially in the basal forebrain or develop behavioral or cognitive abnormalities compared to the wild-type mice or to mice overexpressing human wild-type PGRN, and to develop PGRN overexpressing and deficient cellular models and to utilize these models to study overexpressed and/or endogenous PGRN cellular localizations and protein trafficking and turnover.

      Researcher(s)

      Research team(s)

      Mechanism of dense plaques at the Alzheimer's disease. 01/01/2008 - 31/12/2009

      Abstract

      Amyloid-ß (Aß) aggregation in brain parenchyma as dense-core and diffuse plaques, and in vascular walls, are a major neuropathological feature of Alzheimer's disease. Dense-core plaques are considered neurotoxic. Several lines of evidence suggest that Aß does not aggregate spontaneously in brain but is rather assisted by specific chaperones that help Aß to aggregate into ß-sheets. We recently identified vessels to be a major site where dense-core plaques develop in both transgenic mouse models and patients of Alzheimer's disease, suggesting that vessels are a hot-spot for such Aß assembly-promoting factors. Interestingly, vessels free of Aß deposition have also been shown to have a number of structural microvascular abnormalities in both Alzheimer's patients and transgenic mouse models suggesting that vascular pathology is also important in the pathogenesis of Alzheimer's disease. Utilizing transcriptomic and proteomic analysis, the current project aims to elucidate the mechanism(s) of dense-core plaque formation at vascular sites as well as to understand changes that occur in these vessels prior to plaque deposition in various transgenic mouse models of Alzheimer's disease. These studies would in turn further aid in identifying novel potential therapeutic targets for preventing or treating Alzheimer's disease.

      Researcher(s)

      Research team(s)

      Identification and characterization of new causal genes and risk factors for 'Lewy body' brain diseases. 01/01/2008 - 31/12/2009

      Abstract

      'Lewy body' diseases represent a spectrum of disorders ranging from Alzheimer disease (AD) to Parkinson disease (PD). Dementia with Lewy bodies (DLB) has a central position within this spectrum. It is the second most frequent type of neurodegenerative dementia after AD with a prevelance up to 30% of all dementia patients. Despite its high prevelance, the molecular genetic etiology of the disease remains unknow. We recently identified a new locus for DLB on chromosome 2q35-q36 in a Belgian autosomal dominant DLB family. The identification of the underlying genetic defect will reveal one of the first causal genes for DLB and have a major impact on our understanding of the molecular pathogenesis of DLB. Ultimately these findings will contribute to the development of more accurate diagnostic and therapeutic strategies.

      Researcher(s)

      Research team(s)

      Molecular genetic analysis of Alzheimer dementia. 01/10/2007 - 30/09/2009

      Abstract

      Alzheimer's disease (AD) is the most common form of dementia in the elderly. In the majority of AD patients the molecular cause of neurodegeneration is so far unknown. Once AD appears it can be considered as an end point of several disease processes which impedes the research of the exact etiology. Intermediate phenotypes such as the episodic memory, which change early in the pathological process are more directly under influence of the underlying genetic factors and can therefore support the genetic research of AD. By a molecular genetic approach this project will contribute to the research of the neurodegenerative process in AD and will therefore lead to a better understanding of the etiology of dementia. Genetic association studies on selected candidate genes as well as genomic association studies will be performed in a large and well characterized Belgian AD population. The role of the identified AD risk genes in the conversion of "Mild Cognitive Impairment (MCI)" to AD will be further investigated in MCI patients. Results from the AD research will also be analyzed in a group of healthy individuals coming from a Swedish memory population. Additionally we will identify novel biomarkers in plasma or cerebrospinal fluid using amyloid beta quantifications and proteomics profiling experiments. When genetic informative multiplex families are available, genomic linkage studies will be carried out.

      Researcher(s)

      Research team(s)

      Identification of new genes and risk factors for Parkinson's disease. 01/10/2007 - 30/09/2009

      Abstract

      Genetic susceptibility of complex diseases like Parkinson disease (PD) is due to a different spectrum of sequence variants compared to the classical simple mutations in coding sequences that cause monogenic diseases. Exon and gene copy number variations (CNVs) and variations in regulatory sequences that influence gene expression are major players of this complex mutation spectrum, as reported for SNCA, PARK2 en DJ-1. It is clear that differential expression, either through DNA dosage or regulation of transcription or translation, can lead to variable onset ages, disease progression and phenotypes reported for complex neurological disorders. We therefor extended the molecular genetic analyses of PD from the standard mutation analyses of coding sequences to more complex variations like CNVs and variations influencing gene expression. Currently we are performing an extensive analysis of the SNCA 5'regulatory region. We identify the genetic variants responsible for increased risk of PD through direct sequencing of gDNA of patients and control individuals. The role of PD related variations in the pathogenesis is investigated using reporter gene assays in transfected human neuronal and non-neuronal cell models and other standard molecular biological techniques. Soon we will start a comparable analysis of the PARK2 promoter and other conserved regulatory regions.

      Researcher(s)

      Research team(s)

      Genetic epidemiological analysis of a prospective Alzheimer dementia population. 01/10/2007 - 30/09/2009

      Abstract

      The aim of this project is to contribute to further unravel the etiology and epidemiology of AD and neurodegeneration, using molecular genetics as a tool. We will go through following steps to achieve this: (1) Genetic characterisation and expansion of a Belgian AD patient population. We will perform a mutation analysis of the known dementia genes and an APOE genotyping. Multiplex families and patient-triads will be collected starting from this population. (2) Identification of new causal AD genes, using the positional cloning strategy in collected multiplex families. (3) Identification of new AD risk genes in the patient-triads by use of association studies. We will use family-based (in patient-triads) as well as classical patient/control association studies. (4) Determination of the Ab42/Ab40 ratio in plasma, to identify non-symptomatic at risk individuals and to use as co-variant in association studies.

      Researcher(s)

      Research team(s)

      Elucidation of the role of progranulin (PGRN) in frontotemporal dementia (FTD) with mouse models. 01/10/2007 - 30/09/2008

      Abstract

      Recently, mutations in progranulin (GRN) were identified as the cause of the most common form of frontotemporal dementia (FTD-U). Most of these mutations are null mutations, suggesting that reduced levels of GRN protein are at the basis of the disease pathomechanism. Also recently, the TAR DNA binding protein (TDP43) was identified as a major constituent of the intraneuronal nuclear and cytoplasmic inclusions typically found in FTD-U. This project aims to develop progranulin knockout mice (Grn-/+ and Grn-/-) and human GRN and TDP43 overexpression mouse models that would serve to elucidate whether and how progranulin loss leads to decreased cell survival, specifically of the cortical neurons. Behavioral or cognitive abnormalities compared to the wild-type mice or to mice overexpressing human GRN will also be studied. However, because GRN/Grn is an important gene expressed in a variety of tissues, the targeting construct utilizes a conditional knockout approach that can be used if the constitutive Grn loss is embryonically lethal. Also, targeted Grn ablation in neurons or neuroglia will be studied with this construct. Lastly, we will generate crossbred Grn-/- x TDP43 overexpressing mice to study possibly accelerated TDP43 pathology. These mouse models would serve as both disease model and mechanism model on which novel therapeutic approaches could be tested in the future.

      Researcher(s)

      Research team(s)

      Elucidation of the role of progranulin (PGRN) in frontotemporal dementia (FTD) with cellular models. 01/10/2007 - 30/09/2008

      Abstract

      Progranulin (GRN) is a growth factor involved in tumorogenesis, while loss of GRN leads to frontotemporal dementia (FTD). The precise mechanisms underlying GRN-mediated cell proliferation and neuronal survival as well as a link with TDP43, that is cleaved, phosphorylated and deposited as intraneuronal inclusions in FTD patients, are not well understood. The project aims at developing GRN and TDP43 overexpression and deficient cellular models including primary neuronal cells derived from Grn-/- mice to study the biochemistry and interaction of GRN and TDP43 in disease context. These models will be established using siRNA mediated protein knockdown and expression of tagged/untagged GRN and TDP43 proteins. We will study GRN-mediated cell proliferation as well as other phenotypes using cellular assays such as BrdU proliferation, flow cytometry and caspase-luminescence assays. The established models will also be utilized to study subcellular localization, protein trafficking and turnover of endogenous and/or overexpressed GRN and TDP43 as well as altered signaling pathways. Furthermore the link between GRN deficiency and TDP43 phosphorylation, fragmentation and accumulation will be elucidated in these cell models. Characterization of these cellular models would give us important insights in the mechanisms by which GRN haploinsufficiency causes decreased neuronal survival.

      Researcher(s)

      Research team(s)

      Identification and characterization of new causal genes and risk factors for 'Lewy body' brain diseases. 01/10/2007 - 31/12/2007

      Abstract

      'Lewy body' diseases represent a spectrum of disorders ranging from Alzheimer disease (AD) to Parkinson disease (PD). Dementia with Lewy bodies (DLB) has a central position within this spectrum. It is the second most frequent type of neurodegenerative dementia after AD with a prevelance up to 30% of all dementia patients. Despite its high prevelance, the molecular genetic etiology of the disease remains unknow. We recently identified a new locus for DLB on chromosome 2q35-q36 in a Belgian autosomal dominant DLB family. The identification of the underlying genetic defect will reveal one of the first causal genes for DLB and have a major impact on our understanding of the molecular pathogenesis of DLB. Ultimately these findings will contribute to the development of more accurate diagnostic and therapeutic strategies.

      Researcher(s)

      Research team(s)

      Elucidating the role of Abeta-interacting molecules in the formation of vasocentric plaques in Alzheimer's disease. 01/10/2007 - 31/12/2007

      Abstract

      Amyloid-ß (Aß) aggregation in brain parenchyma as dense-core and diffuse plaques, and in vascular walls, are a major neuropathological feature of Alzheimer's disease. Dense-core plaques are considered neurotoxic. Several lines of evidence suggest that Aß does not aggregate spontaneously in brain but is rather assisted by specific chaperones that help Aß to aggregate into ß-sheets. We recently identified vessels to be a major site where dense-core plaques develop in both transgenic mouse models and patients of Alzheimer's disease, suggesting that vessels are a hot-spot for such Aß assembly-promoting factors. Interestingly, vessels free of Aß deposition have also been shown to have a number of structural microvascular abnormalities in both Alzheimer's patients and transgenic mouse models suggesting that vascular pathology is also important in the pathogenesis of Alzheimer's disease. Utilizing transcriptomic and proteomic analysis, the current project aims to elucidate the mechanism(s) of dense-core plaque formation at vascular sites as well as to understand changes that occur in these vessels prior to plaque deposition in various transgenic mouse models of Alzheimer's disease. These studies would in turn further aid in identifying novel potential therapeutic targets for preventing or treating Alzheimer's disease.

      Researcher(s)

      Research team(s)

      Institutional funds VIB8 2007-2011: Department of Molecular Genetics. 01/01/2007 - 31/12/2011

      Abstract

      The VIB Department of Molecular Genetics (DMG) is specialized in the genetic analysis of complex neurological and neuropsychiatric diseases. All these diseases are multifactorial in nature i.e. they are expressed due to the interplay of genes and environment. In some of these diseases the inheritance pattern is mainly Mendelian with gene defects in single genes. In others only in a small fraction of patients genetic factors are apparent. In the latter cases, several families with Mendelian inheritance have been identified (= monogenic component). In the majority of the cases the disease expression is modulated by complex gene-gene and gene-environment interactions. Our major aims are to identify novel molecular mechanisms for disease causation and effective drug treatment for these devastating diseases. We use different genetic and genomic approaches to identify genes (causal mutations) and genetic risk factors (predisposing polymorphisms) based on molecular genetics, genetic epidemiology and functional genomics approaches. The contribution of a disease gene is estimated in population and hospital based patient series. Also, we will examine these genes and risk factors in relation to other genes as well as to environmental risk factors. To understand the pathogenic role of these mutations and polymorphisms, we will use cellular systems, mouse and Drosophila models. Also, the observed biological phenomena can be compared directly with those observed in patients. Finally, these models should allow us to test for treatment approaches. There are currently 5 research groups within the department that are each headed by a faculty member: Neurodegenerative Brain Diseases (Christine Van Broeckhoven PhD DSc), Neurogenetics (Peter De Jonghe MD PhD), Peripheral Neuropathies (Vincent Timmerman PhD), Molecular Neurogenomics (Albena Jordanova PhD) and Applied Molecular Genomics (Jurgen Del-Favero PhD).

      Researcher(s)

      Research team(s)

      An integrated approach to the unraveling of the pathogenesis of CNS and PNS neurodegenerative disorders. 01/01/2007 - 31/12/2011

      Abstract

      This network project is designed to apply the unique information provided by sequencing of the human genome to further the understanding of and to develop treatments for neurodegenerative diseases. The association in the proposed network of research groups in clinical research, human genetics and genomics, cell biology, proteomics, bioinformatics, and model organisms (mice, zebrafish and Drosophila), will create an integrated network that should allow identification of novel disease genes, determination of their biological functions, establishing their role in pathophysiological processes and identification of novel avenues for early diagnosis, treatment and prevention. The network will focus its research activities on diseases of the central nervous system (CNS) such as Alzheimer disease, Parkinson disease, frontotemporal dementia and related diseases; and diseases of peripheral nervous system (PNS) such as peripheral motoneuronopathies, amyotrophic lateral sclerosis and related disorders.

      Researcher(s)

      Research team(s)

      Molecular genetics of Alzheimer's disease: an integrated genetic, genomics and neuropathological approach. 01/01/2007 - 31/12/2010

      Abstract

      The general aim of this project is to contribute to a bettter knowledge of the genetic etiology of AD. This knowledge is expected to provide a better insight in the genetic risk profile of a human being (early detection) and in the biology of the disease process in brain (neuropathology/biology). Specific aims: 1. Collection of materials for genetic studies of AD patients and families. 2. Genetic characterization of AD patients and genotype-phenotype correlations. 3. Identification of novel chromosomal loci and genes for AD 4. Identification of novel risk and protection factors for AD 5. Neuropathological and neurobiological analysis of AD mutations/genes.

      Researcher(s)

      Research team(s)

      Identification and characterization of the genetic causes of the tau-negative frontotemporal demention. 01/01/2007 - 31/12/2008

      Abstract

      Frontotemporal dementia (FTD) is the second most common cause of neurodegenerative dementia in people younger than 65 years. Clinically FTD is characterized by profound disturbances in behavior, personality and language and may be associated with parkinsonism or motor neuron disease. Up to 50% of FTD patients have a positive family history for dementia and in the majority of these families the disease is inherited in an autosomal dominant fashion. FTD has proven to be genetically heterogeneous with the identification of mutations in the microtubule associated protein tau gene (MAPT) on chromosome 17q21, in the charged multivesicular body protein 2B or chromatin modifying protein 2B gene (CHMP2B) located in the pericentromeric region of chromosome 3, and in the valosin containing protein gene (VCP) on chromosome 9p13-p12. Also, evidence has accumulated for a second gene at the 17q21 region that is associated with non-tauopathy FTD characterized by ubiquitine-immunoreactive neuronal inclusions of unknown nature (FTDU-17). The aim of this research project is the identification of the genetic causes of tau-negative FTD on chromosome 17, chromosome 3, and chromosome 9.

      Researcher(s)

      Research team(s)

      Study of the function of progranulin in frontotemporal dementia via cellular and mouse models. 01/01/2007 - 30/09/2007

      Abstract

      This PhD project intends to study the role of progranulin (PGRN) in frontotemporal demntia (FTD) with both in vitro experiments and in vivo mouse models. In vitro RNA interference (RNAi) techniques will be utilized to study if reduced PGRN expression causes decreased survival of cultivated neuronal cells and primary neurons. In vivo a PGRN constitutive and conditional knock-out mouse model will be developed. On these mice I will study the function of PGRN in brain and how PGRN loss causes neurodegeneration specifically of the neurons of the forebrain. Finally, primary neuronal cultures derived from different regions of rodent brain will also be examined ex vivo to study PGRN expression patterns and to elucidate why loss of PGRN is more critical to neurons of the forebrain.

      Researcher(s)

      Research team(s)

      Molecular genetic research of Alzheimer dementia. 01/01/2007 - 30/09/2007

      Abstract

      Alzheimer's disease (AD) is the most common form of dementia in the elderly. In the majority of AD patients the molecular cause of neurodegeneration is so far unknown. Once AD appears it can be considered as an end point of several disease processes which impedes the research of the exact etiology. Intermediate phenotypes such as the episodic memory, which change early in the pathological process are more directly under influence of the underlying genetic factors and can therefore support the genetic research of AD. By a molecular genetic approach this project will contribute to the research of the neurodegenerative process in AD and will therefore lead to a better understanding of the etiology of dementia. Genetic association studies on selected candidate genes as well as genomic association studies will be performed in a large and well characterized Belgian AD population. The role of the identified AD risk genes in the conversion of "Mild Cognitive Impairment (MCI)" to AD will be further investigated in MCI patients. Results from the AD research will also be analyzed in a group of healthy individuals coming from a Swedish memory population. Additionally we will identify novel biomarkers in plasma or cerebrospinal fluid using amyloid beta quantifications and proteomics profiling experiments. When genetic informative multiplex families are available, genomic linkage studies will be carried out.

      Researcher(s)

      Research team(s)

      The identification of genes involved in variation in episodic memory and Alzheimer dementia. 01/10/2006 - 30/09/2009

      Abstract

      Alzheimer's disease (AD) is characterized by a progressive deterioration of cognition, of which loss of memory for specific personal events is the most prominent. The pathological process leading to AD is already taking place years before the disease becomes evident. In this stage people may show signs of mild cognitive impairment. We aim to find genetic factors that may affect the risk to get AD, and we want to study if these genetic risk factors already differentiate between good and poor memory performance before the disease becomes evident. Knowledge about genes implicated in AD and memory will clarify which molecular processes are crucial in the development of AD, which will help setting the targets for future development of medicine. Further, we want to examine correlations between newly identified genetic risk factors, poor memory performance or AD, and changes in biomarkers, such as brain volume or activity on MRI scans, or composition of cerebrospinal fluid. If we are able to identify genetic factors that increase risk of AD and are correlated with specific biomarker profiles, this might help in future research to determine risk profiles for prevention strategies.

      Researcher(s)

      Research team(s)

      Positional cloning and characterization of novel dementia genes. 01/10/2006 - 30/09/2008

      Abstract

      The most frequent causes of dementia are neurodegenerative brain diseases e.g. Alzheimer's disease and frontotemporal dementia. Genetic factors play a key role and to date, 5 dementia genes are identified. However, not all patients with familial dementia have a mutation in one of the known genes so that other, yet unknown dementia genes exist. The aim of this project is to identify novel dementia genes using positional cloning techniques. This will substantially contribute to our understanding of the biological processes leading to dementia and will ultimately help developing of therapeutic strategies.

      Researcher(s)

      Research team(s)

      A new mouse model for Alzheimer's disease : diffuse and truncated amyloïd ß42 pathology. 01/10/2006 - 30/09/2008

      Abstract

      Most cases of neurodegenerative brain diseases like Alzheimer's Disease (AD) or Parkinson's disease (PD) appear sporadically, whereas familial cases are rare. The genetic factors involved are, for example, APP- and presenilin genes in AD and a-synuclein and parkin genes in PD. Mutations in these genes will be studied in vitro, by cell culture experiments, as well as in vivo, in transgenic mouse models. It is expected that these studies will allow us to improve our understanding of the pathogenic mechanisms of the genetic as well as the sporadic forms of these diseases.

      Researcher(s)

      Research team(s)

      Molecular genomics of neurodegenerative brain diseases. 01/10/2006 - 31/03/2007

      Abstract

      This research project aims at the identification of genetic defects in novel loci that were identified in previous molecular genetic studies of patients with neurodegenerative brain diseases. Identification of novel genetic defects will result in better understanding the pathobiology of neurodegenerative brain diseases, that will dramatically increase in frequency in the near future due to the aging of western societies.

      Researcher(s)

      Research team(s)

      VIB-Role of the GluR2 subunit of the AMPA receptor in the pathogenesis of ALS. 01/08/2006 - 31/07/2008

      Abstract

      Evidence suggests that excitotoxicity plays a role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Excitotoxic motor neuron death is mediated by entry of calcium (Ca2+) through the AMPA-type of glutamate receptor (Glu). The Ca2+ permeability of the AMPA receptor ion channel is determined by the presence of the GluR2 subunit: the more GluR2 is present in the complex, the lower its permeability to Ca2+. Understanding the regulation of GluR2 expression may therefore add to our insights into the pathogenesis of ALS, and in particular the selectivity of motor neuron death in ALS. Here, we will study three aspects of the regulation of GluR2 expression. We study the mechanism of the glial-neuronal regulatory interaction. We investigate the role of VEGF in GluR2 expression in vitro and in vivo. Finally, we evaluate the possible role of GluR2 expression levels in human sporadic ALS by performing a genetic association study of sporadic ALS and GluR2 promoter polymorphisms.

      Researcher(s)

      Research team(s)

      Transgenic Service Facility: support central facilities. 01/05/2006 - 31/12/2006

      Abstract

      The Transgenic mice Service Facility is centered on several aspects of Mouse transgenesis and is operational in the Specific Pathogen Free facility of the Mouse housing facility of the University of Antwerp ¿ CDE: production of genetically modified mice via pronuclear injections, production of knock-out ands knock-in clones via embryonic stem cells, re-derivation of non-SPF mice and cryopreservation van important mouse lines. At the end of 2007 the TgSF activities were stopped.

      Researcher(s)

      Research team(s)

      Molecular genetic service spin-off: Multiplex PCR algorithm in DNA profiling. 01/02/2006 - 31/12/2010

      Abstract

      This project is centered round 3 defined goals: providing non-standard fee-for-service expertise (services); technology development to create new products and/or methods (technology development); and molecular genetics research related to complex diseases in general and psychiatric diseases in particular (complex genetics). Through our services we provide third parties the possibility to use our genetic analysis expertise, like sequence based SNP discovery and genotyping STR markers and SNPs on a fee-for-service basis. To provide these genetic services we use the state of the art platform available in the Genetic Service Facility (GSF) of the VIB8-Department of Molecular Genetics (see also project ID: 20983). The goal of the technology development is to create novel products (e.g. software and diagnostic kits) and methods resulting from the expertise present in the Applied Molecular Genomics research group and is at the moment mainly focused on our proprietary multiplex PCR technology. The complex genetics research goal is focusing on the identification of susceptibility genes for schizophrenia and affective disorders through the use of family and population based genetic analysis.

      Researcher(s)

      Research team(s)

        Molecular genetics of frontal temporal dementia : identification of causal and genetic risk factors. 01/01/2006 - 31/12/2009

        Abstract

        The general aim of this project is to contribute to a better understanding of the genetic etiology of familial and sporadic FTD. Specific aims are: 1) Collection of FTD patients and families, 2) Identification of the genetic defect in FTDU-17, 3) Identification of novel FTD loci and 4) Genetic association study of MAPT in FTD patient populations.

        Researcher(s)

        Research team(s)

        Center of excellence NEURO. 01/01/2006 - 31/12/2007

        Abstract

        The research activity in the research excellence centre NEURO focuses on molecular genetics and clinical neurology of neurodegenerative diseases comprising diseases of the central nervous system such as Alzheimer disease, Parkinson disease, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis and related diseases; and of the peripheral nervous system such as motor- and/or sensory neuropathies and related disorders. The centre brings together basic and clinical researchers from the Department of Molecular Genetics, VIB, and the Institute Born-Bunge, representing two major neuroresearch activities at the University of Antwerp. The general aim of the excellence centre aims at clarifying a series of fundamental questions related to the pathophysiological processes underlying neurodegenerative diseases. More specifically, the elucidation of biological disease pathways by identifying novel genes and genetic risk factors and modifiers of genetic function, by analysing the functional networks in which proteins encoded by these genes are operating, and ultimately, by providing novel avenues for early diagnosis, prognosis, prevention and treatment.

        Researcher(s)

        Research team(s)

        Presenilin 1 induced tau pathology: biochemical and neuropathological characterisation in humans and mouse models. 01/01/2006 - 31/12/2006

        Abstract

        Presenilins (PS 1 and 2) are integral components of the gamma-secretase complex which is responsible for the cleavage of a number of transmembranous proteins including amyloid precursor protein (APP) and Notch. Mutations within PS1 are primary cause of familial Alzheimer's disease (FAD). It is assumed that PS mutations cause FAD due to the "amyloid cascade" where Aß accumulation lies upstream of tau phosphorylation and neurodegeneration. However, increasing evidence suggests that PS might directly interact with tau and tau kinases. Our departement identified a PS1 mutation (G183V) causing frontotemporal dementia (FTD) of the Pick's disease type. In this disease, patients present with progressive changes in behavior or language dysfunction and it is an important cause of dementia in patients younger than 65 years of age.The aim of this project is to study the underlying mechanisms of tau accumulation due to PS1 G183V in cellular and mouse models. These models might shed light on how a pathological PS1 mutation could trigger tau pathology and/or neurodegeneration.

        Researcher(s)

        Research team(s)

        VIB-Frontotemporal dementia with ubiquitin positive neuronal inclusions (FTD-U). 01/11/2005 - 31/10/2007

        Abstract

        In this project our main focus will be on the identification and characterization of the genetic defect underlying the pathology in frontotemporal dementia (FTD) characterized by tau-negative but ubiquitine-positive staining neuronal inclusions (FTD-U), more specifically FTD-U linked to chromosome 17q21 or FTDU-17. FTD dementias are the most frequent form of neurodegenerative dementias next to Alzheimer dementia (AD), FTD-U represents a major FTD subform, but its frequency is not well known though likely underestimated. Currently, we have no clear knowledge of the molecular cause of FTD-U neurodegeneration, though it would allow modelling the pathophysiology in cells and animal models. These models, as for other dementias like AD, form the basis for research towards understanding the biology of neurodegeneration per se and development of effective therapies. FTD represents approximately 5% of all dementia patients and 10-20% of patients with an onset age below 65 years. FTD patients present personality changes and disinhibited behaviour, often accompanied by gradual and progressive language dysfunctions. Neuropathological examination identified 3 broad groups: patients with tau-positive pathology or FTD¿, with tau-negative but ubiquitine-positive pathology or FTD-U and those lacking distinctive histopathology or DLDP. In general only a third of all FTD patients had FTD¿, conversely the relative contributions of FTD-U and DLDH significantly varied. A positive family history of dementia is found in approximately 40% of FTD patients and in the majority of these patients the disease is inherited as an autosomal dominant trait. Recent studies have shown that 10-43% of all familial FTD patients are associated with mutations in the gene encoding the tau protein (MAPT) located at 17q21. To date, 36 different MAPT mutations have been identified in 106 dementia families worldwide. However, in at least 4 autosomal dominant FTD families linked to 17q21 mutations in MAPT were not identified. The latter stimulated many researchers to analyse extended FTD families with unknown genetic cause, resulting in an increasing number of FTDU-17 families suggesting a higher frequency than previously predicted. Also, while more pathological data became available it seems that the majority ¿ if not all ¿ of these families belong to the FTD-U subtype. Together, the current data indicate that identification of the underlying gene defect in FTDU-17 might significantly contribute to our understanding of the pathomechanism leading to neurodegeneration in this dementia subtype. We will use molecular genetic and pathological studies to identify the genetic defect in FTDU-17. We previously defined the smallest candidate region of 4.8 cM in one Dutch-Netherlands FTDU-17 family 1083. Recently we identified 3 Dutch-Belgian FTDU-17 families and showed by haplotype analysis a founder effect in Flanders, the Dutch-speaking region of Belgium. In addition, we aim at characterizing the inclusion pathology and proteinopathy by immunohistochemistry and/or by mass spectrometric analysis of laser-dissected and enriched ubiquitin-positive aggregates from frozen FTDU-17 brains. We expect that the identification of the FTDU-17 defect will contribute to the differential diagnosis of FTD, to the generation of cellular and animal models for FTDU-17 and finally to a better understanding of the neurodegenerative process in general that should contribute to the development of a more effective therapy for dementia.

        Researcher(s)

        Research team(s)

        Molecular genetics of neurodegenerative brain diseases. 01/10/2005 - 30/09/2007

        Abstract

        The aim of this project is the identification of genes and risk factors for Parkinson's disease, parkinsonism and mixed parkinsonism and dementia, e.g. dementia with Lewy bodies (DLB). Families and patient populations are used for the identification of these genetic factors in respectively linkage and association studies. Family AD-V, a Flemish multiplex family with parkinsonism and dementia, was collected when the index patient of this family screened negative for mutations in the known dementia genes and SNCA, PARK2, DJ1 and the exons of LRRK2 known to have mutations. DNA of 22 family members, including 8 patients, was collected and a genome wide search was started. We found suggestive linkage to chromosome 2. Haplotype analysis and the identification of obligate recombinants delineated a minimal candidate region of 9.2 Mb. 73 genes are located within the candidate region. These genes were prioritized based on their expression in brain and their biological relevance towards DLB pathogenesis. Using direct sequence analysis all exons, intron-exon boundaries and the promoter of these genes are screened for mutations. Comparison of the sequences of patients and control individuals enables the identification of a pathogenic mutation. Characterization of the normal and mutated functions of the causal gene will be done in vitro in transfected cells and in vivo in relevant animal models. The type of mutation and gene will determine the appropriate methodology for functional work. Genetic risk factors for PD are also studied. Through collaborations we have DNA samples of PD patients from the Middelheim Prospective Dementia study (Engelborghs et al., 2003) and from a Belgian retrospective epidemiological patient-control study designed to identify environmental and genetic risk factors for PD. Association studies are based on single nucleotide polymorphism (SNP) analysis. The SNPs are known SNPs or SNPs identified by a pilot study of 25 patient triads. Based on these SNPs the haplotype structure of each candidate gene is determined and haplotype tagging SNPs (htSNPs) are selected that capture (sub)haplotype diversity of the candidate genes at most. HtSNPs are tested in patients and control individuals using high throughput genotyping techniques and subsequent haplotype analysis leads to the identification of (sub)haplotypes influencing PD susceptibility. Further sequence analysis of the minimal associated region can identify variants functionally relevant for PD pathogenesis.

        Researcher(s)

        Research team(s)

        Identification of new genes and risk factors for Parkinson's disease. 01/10/2005 - 30/09/2007

        Abstract

        Parkinson's disease (PD) is the second most common progressive, neurodegenerative brain disorder. The majority of the patients are sporadic, though a minority (~15%) has a familial history of PD. Although several genes are known for PD, another 80% of the genetic variation in PD is caused by unknown genetic factors. We will seek new causal genes and risk genes through linkage studies in PD families and patient/control association studies respectively.

        Researcher(s)

        Research team(s)

        Genetic epidemiological analysis of a prospective Alzheimer dementia population. 01/10/2005 - 30/09/2007

        Abstract

        The aim of this project is to contribute to further unravel the etiology and epidemiology of AD and neurodegeneration, using molecular genetics as a tool. We will go through following steps to achieve this: (1) Genetic characterisation and expansion of a Belgian AD patient population. We will perform a mutation analysis of the known dementia genes and an APOE genotyping. Multiplex families and patient-triads will be collected starting from this population. (2) Identification of new causal AD genes, using the positional cloning strategy in collected multiplex families. (3) Identification of new AD risk genes in the patient-triads by use of association studies. We will use family-based (in patient-triads) as well as classical patient/control association studies. (4) Determination of the Ab42/Ab40 ratio in plasma, to identify non-symptomatic at risk individuals and to use as co-variant in association studies.

        Researcher(s)

        Research team(s)

        VIB-Genotyping assays for single-nucleotide polymorphisms (SNPs) associated with Parkingson's disease - 'MJFF Validation Study'. 01/09/2005 - 31/12/2005

        Abstract

        The purpose of the MJFF Validation Study is to confirm whether 13 SNPs identified in a previously funded MJFF genome-wide SNP association study ("Perlegen/Mayo Study") are associated with Parkinson's disease. The strength of the Validation Study lies in the use of several independent case-control populations available through the MJFF-funded Edmond J. Safra Genetics Consortia and other sources to provide a rigorous validation of the Perlegen/Mayo Study SNP findings. Results (positive or negative) from this collaborative study will be submitted for publication as a group. Through this unified effort, the MJFF wishes to provide a scientifically appropriate test of the original Perlegen/Mayo Study findings and ultimately give greater clarity and insight into the genetic contribution to Parkinson's disease.

        Researcher(s)

        Research team(s)

        Molecular characterization of frequent neurological disorders in the Bulgarian population. (A. JORDANOVA, Bulgarije) 01/04/2005 - 30/09/2005

        Abstract

        This study relates to the understanding of degeneration processes in the peripheral nervous system based on genes identified for inherited peripheral neuropathies, i.e. Charcot-Marie-Tooth disease and related disorders. These diseases have a juvenile but also a major age-related component with impact on quality of life as well as socio-economical consequences. Areas of application of the fundamental research performed in this network are within the domain of biomedicine, i.e. diagnosis and treatment of age related diseases. The project aims further characterization of molecular defects in known genes and identification of novel loci and genes, that may cause two of the most common neurological disorders in Bulgaria and worldwide : IPN and epilepsy.

        Researcher(s)

        Research team(s)

        VIB-Genetic Service Facility: Support Centralized Service Facilities. 01/01/2005 - 31/12/2017

        Abstract

        The GSF is a centralized facility within the VIB Department of Molecular Genetics (DMG) located at the University of Antwerp. The DMG GSF is subsidized by the institute VIB to provide capacity for standard Sanger sequencing services to VIB scientists at marginal costs. The DMG GSF has a competitive position because of high processing capacity and high quality service. With an optimized database system LIMS (Laboratory Information Management System), ELN (Electronic Laboratory Notebook) and GLP ("good laboratory practice") environment, the majority of the data processing is executed automatically and in optimal conditions. The DMG GSF also offers consultation and assistance upon customer's request. Years of collaboration with industrial partners resulted in a setting and a methodology where confidentiality of the data is assured. For the Sanger sequencing services, the DMG GSF is equipped with three 3730 XL 96-capillary DNA Analyzers (Life Technologies), three automated workstations (Biomek NX, Biomek NXP and Biomek FXP, Beckman Coulter) for automatic pre- and post- processing of samples, including purification, DNA whole genome amplification, aliquoting, dilution, normalization and pooling of samples. On the same platform, the VIB DMG can also provide non-standard services on a custom-basis for the analysis of mono- or multiplex STR markers, whole-genome wide STR markers or dosage analysis of CNV. The VIB DMG is also Equipped with three MiSeq and one NextSeq500 systems (Illumina) which allow NGS services including targeted, whole exome (WES) and RNA sequencing.

        Researcher(s)

        Research team(s)

        Pathogenesis of CNS neurodegeneration: molecular genetic analysis of Alzheimer's and frontotemporal dementia. 01/01/2005 - 31/12/2007

        Abstract

        Neurodegenerative dementias are the most common diseases of the aging population representing major medical, social and economic problems. The disease processes are not yet fully understood and no effective treatment is available. This project aims at identifying and characterizing novel neurodegenerative dementia genes more particularly of Alzheimer's and frontotemporal dementias. This will help to understand pathological processes and identify novel drug targets.

        Researcher(s)

        Research team(s)

        Molecular genetics of idiopathic epilepsies. 01/01/2005 - 31/12/2006

        Abstract

        Epilepsy is one of the most common neurologic disorders, with a cumulative life-time incidence of about 3%. The epilepsies can be classified according to their etiology. For the idiopathic epilepsies there is no underlying cause other than a possible hereditary predisposition. Molecular genetic research has already identified thirteen genes in which mutations cause epilepsy. The fact that mutations in these genes are only found in a limited part of the families indicates that the idiopathic epilepsies are genetic heterogeneous. Therefore, further research towards new genes involved in these epilepsies is essential. The main purpose of this project is the identification of new loci and genes in which mutations cause an epileptic phenotype. Initially large multiplex families are studied. In these families the responsible genetic locus is identified by linkage analysis and the candidate genes in the region are screened for disease-related mutations. For nuclear families or isolated patients we use a candidate gene approach. The selection of the candidate genes is based on their homology with genes identified in epileptic phenotypes of man and mouse. Also known epilepsy genes are analyzed in families with a similar phenotype, which gives an indication of the frequency of mutations in that gene. This allows us to make genotype-phenotype correlations. By extending the mutation analysis to other epileptic phenotypes we investigate whether mutations in the gene cause other types of epilepsy or if they act like susceptibility factors. We will also investigate the functional effects of the identified mutations in in vitro and in vivo systems. Electrophysiological experiments are used to analyze mutations in subunits of ion channels. Mouse models will help to reveal the effect of the mutation on neuronal circuits or an entire organism.

        Researcher(s)

        Research team(s)

        Identification and characterization of the defect for ubiquitine-positive, tau-negative frontotemporal dementie linked to chromosome 17q21 (FTDU-17). 01/01/2005 - 31/12/2006

        Abstract

        Frontotemporal dementia (FTD) is the second most common cause of neurodegenerative dementia in people younger than 65 years. Clinically FTD is characterized by profound disturbances in behavior, personality and language and may be associated with parkinsonism or motor neuron disease. Up to 50% of FTD patients have a positive family history for dementia and in the majority of these families the disease is inherited in an autosomal dominant fashion. So far only mutations in the microtubule associated protein tau gene (MAPT) on chromosome 17q21 have been identified for FTD linked to chromosome 17, with a frequency of 10 tot 43% in familial FTD. In a number of autosomal dominant FTD families linked to 17q21 mutation analysis failed to identify any MAPT mutations (FTDU-17). With this research project we aim to investigate the genetic causes of FTDU-17 trough positional cloning strategy in autosomal dominant FTD families.

        Researcher(s)

        Research team(s)

        Identification of new genes and risk factors for Alzheimer's disease. 01/01/2005 - 30/09/2005

        Abstract

        Dementia is a progressive, neurodegenerative brain disease, characterized by a cognitive decline of the patient. Dementia is most common in the elderly and is a growing health and economical problem. Furthermore, there is still no therapy that can reverse or even stop this devastating disease. Alzheimer's disease (AD) is the most frequent type of dementia. Though most of the patients show the first signs of AD during mid to late adult life, there is a small group of patients that present with an earlier onset. In the latter, there is often a familial predisposition of AD. Positional cloning in these rare families has led to the identification of 3 causal genes for autosomal dominant forms of AD (amyloid precursor protein, APP; presenilin 1 and 2, PS1 and PS2). In addition to these causal genes, a risk gene for AD has been identified (apolipoprotein E, APOE). Together, these 4 genes account for only 30% of the genetic variation seen in AD. Furthermore, there are still families with autosomal dominant AD without mutations in the known dementia genes. The aim of this project is to contribute in unravelling the etiology and epidemiology of AD and neurodegeneration, using molecular genetics as a tool. We will go through following steps to achieve this: (1) Genetic characterisation and expansion of a Belgian AD patient population. We will perform a mutation analysis of the known dementia genes and an APOE genotyping. Multiplex families and patient-triads will be collected starting from this population. (2) Identification of new causal AD genes, using the positional cloning strategy in collected multiplex families. (3) Identification of new AD risk genes in the patient-triads by use of association studies. We will use family-based (in patient-triads) as well as classical patient/control association studies. (4) Determination of the Ab42/Ab40 ratio in plasma, to identify non-symptomatic at risk individuals and to use as co-variant in association studies.

        Researcher(s)

        Research team(s)

        Functional genomics of complex brain diseases. 01/10/2004 - 30/09/2008

        Abstract

        Complex diseases often represent a group of clinically similar conditions with heterogeneous aetiologies due to an interplay of genetic and environmental factors. Multiple studies have demonstrated that independent of causal mutations, variations in regulatory regions leading to variable gene expression of functional candidate genes, can be key determinants of disease development. Our first objective is therefore, a systematic screening for polymorphisms associated with increased disease risk in the regulatory regions of candidate genes for Alzheimer dementia (AD) and other complex disorders like bipolar disorder (BP). Consequently, the effect of these promoter variations on transcriptional regulation will be studied using luciferase reporter gene analyses and the factors involved in allele-specific expression characterised using electrophoretic mobility shift assays (EMSA), DNaseI footprinting (DF), database searches and comparative sequence analysis in different species. The functionality of the candidate binding proteins will be tested by competitive EMSA en DF experiments. Interference and protection assays as well as systematic mutation analysis will provide further information on the nucleotides involved in DNA-protein interaction. When an unknown protein binds the target elemënt,` the gene encoding this protein will be cloned by purification of the protein followed by mass spectrometry and sequencing, database searches, in vitro expression library screening or mammalian expression cloning. Currently, we are analysing the EGAD-related PSENI promoter variations using the strategy described above. When optimised and proven to be successful for the analysis of the PSENI promoter, this strategy will be applied to characterise differential transcription effects in other AD genes and candidate genes for other complex diseases like BP.

        Researcher(s)

        Research team(s)

        Molecular genetic analyses of chromosome 17-linked frontotemporal dementia and related neurodegenerative brain diseases. 01/10/2004 - 30/09/2007

        Abstract

        The aim of this project is to identify the genetic defect responsible for tau-negative FTD at 17q21. It is expected that the identification of this genetic defect will greatly enhance our understanding of the biochemical processes involved in FTD pathology. Extensive molecular genetic analysis of MAPT, the most important candidate gene at 17q21, will also provide valuable information on FTD related tauopathies such as AD, PSP and CBD. The objectives of this project are: 1) Identifying the genetic defect responsible for chromosome 17-linked tau negative FTD, 2) Characterization of the genomic organization of the MAPT region with respect to the chromosome 17q21 low-copy repeats, 3) Constructing a complete SNP and haplotype map of the MAPT genomic region and Refining the genetic association of MAPT haplotype H1 in PSP and related tauopathies.

        Researcher(s)

        Research team(s)

        ICP Ph.D. scholarship Alice Matimba: Pharmacogenetics of genes important for drug absorption, distribution, metabolism, excretion and toxicology (ADMET) in African populations and evolutionary implications of interethnic genetic variability. 01/10/2004 - 30/09/2007

        Abstract

        In the Molecular Genetics department VIB8 the focus is on the identification of genes and/or risk factors for complex brain diseases e.g. Alzheimer's dementia, psychiatric diseases and idiopathic epilepsies. These genetic factors can be used in pharmacogenetics to define genetically more homogeneous patient groups in clinical studies of drug response and side effects. To allow rapid and efficient identification of genetic factors for complex diseases and analysing them in large samples, the department of Molecular Genetics has built a central core facility for high-throughput genetic analyses using modern genetic techniques e.g. Pyrosequencing and Sequenom for SNP analyses, capillary sequencers, robots, etc.. (see http://www.vibgeneticservicefacility.be/). In addition a bioinformatics group is active in data analysis (LIMS) by developing in-house software tools e.g. novoSNP for automatic SNP detection in sequence traces, SNPbox for automatic primer design for large throughput SNP detection or sequencing. These technology and information platforms will be important in the pharmacogenetics project aiming at analyzing genes important for drug absorption, distribution, metabolism, excretion and toxicology (ADMET) in African populations and evolutionary implications of interethnic genetic variability.

        Researcher(s)

        Research team(s)

        Positional cloning and characterization of novel dementia genes. 01/10/2004 - 30/09/2006

        Abstract

        The most frequent causes of dementia are neurodegenerative brain diseases e.g. Alzheimer's disease and frontotemporal dementia. Genetic factors play a key role and to date, 5 dementia genes are identified. However, not all patients with familial dementia have a mutation in one of the known genes so that other, yet unknown dementia genes exist. The aim of this project is to identify novel dementia genes using positional cloning techniques. This will substantially contribute to our understanding of the biological processes leading to dementia and will ultimately help developing of therapeutic strategies.

        Researcher(s)

        Research team(s)

        Identification of susceptibility genes for affective disorders. 01/10/2004 - 30/09/2006

        Abstract

        This PhD project aims to identify susceptibility genes that play a role in the etiology of the psychiatric disorders schizophrenia (SZ) and bipolar disorder (BP). Both are severe psychiatric disorders with a worldwide prevalence of about 1%. Bipolar disorder is a mood disorder characterized by the cyclic alteration of manic and depressive periods, schizophrenia is characterized by the occurrence of psychoses (periods in which contact with reality is disturbed), affective and cognitive symptoms. These are complex disorders, meaning that they are caused by an interaction of different genetic and environmental factors. Despite the high prevalence, morbidity and socio-economical costs, the pathophysiology and etiology of BP and SZ are still unknown. In this project we will use a positional cloning strategy. By performing a complete genome scan we will be able to determine chromosomal regions that show linkage with the disorders and positional candidate genes will be evaluated for their contribution to the etiology of BP and SZ through association studies. Also already known functional candidate genes will be analyzed using population based association studies. For the genome scan we have access to a unique family-based patient population from the Skellefteå region in the province of Västerbotten (northern Sweden). This Skellefteå population is a geographically isolated population, founded in 1320 and characterized by low immigration and emigration and a high expansion rate. For the association studies we have patient-control populations existing of 276 SZ patients and 500 non-related healthy controls and 276 BP patients and 500 non-related healthy controls.

        Researcher(s)

        Research team(s)

          Identification of biomarkers for affective disorder by means of suppressive subtraction hyhridisation. 01/10/2004 - 30/09/2006

          Abstract

          Bipolar disorder (BP) is a severe psychiatric condition characterised by periods of mania and depression. The infliction is devastating for patient and his surroundings, on average 10 to 20% of the patients untimely die by suicide. BP has a lifetime prevalence of 0,5 ' 1,5%. Family, twin and adoption studies have shown that BP has a significant genetic component. Several linkage and association studies identified candidate susceptibility genes and candidate loci but till now none of these yielded a true disease-causing gene. The real problem of this disorder lies within the treatment. The evaluation period for subscribed medicines for a depressive period is 4 to 6 weeks, after witch another treatment can be tested when the previous one has proven to be ineffective. In 20% of the cases no effective treatment can be found within 2 ' 3 years. Moreover the effectiveness of mood stabilizing treatment such as the treatment with lithium, carbamazepine or valproate can only be evaluated when proven ineffective, when a patient refalls into an affective disordered condition. The goals of the proposed research is to discover biomarkers for BP, which can be used to determine differences in gene expression profiles between patients and controls. Subsequently these biomarkers will be used to determine a difference between the various subtypes of the disease, and between the different affective periods of the disease. These biomarkers will be obtained by a `Suppression Subtractive Hybridisation' (SSH) of post mortal hippocampal, frontal lobe tissue, whole blood and lymphoblast cells. The analyses of these subtracted libraries will result in a list of differential expressed genes between patients and controls. With this information answers will be sought for questions like: which genes participate in the disease pathways, what are the gene expression differences between patient and control, what are the gene expression differences between the various subtypes and different affective periods of the disorder, which connections can be made between gene expression and the different genes and what are the parallels between the expression in brain and in blood?

          Researcher(s)

          Research team(s)

          A new mouse model for Alzheimer's disease : diffuse and truncated amyloïd ß42 pathology. 01/10/2004 - 30/09/2006

          Abstract

          Most cases of neurodegenerative brain diseases like Alzheimer's Disease (AD) or Parkinson's disease (PD) appear sporadically, whereas familial cases are rare. The genetic factors involved are, for example, APP- and presenilin genes in AD and a-synuclein and parkin genes in PD. Mutations in these genes will be studied in vitro, by cell culture experiments, as well as in vivo, in transgenic mouse models. It is expected that these studies will allow us to improve our understanding of the pathogenic mechanisms of the genetic as well as the sporadic forms of these diseases.

          Researcher(s)

          Research team(s)

          Identification of a gene for bipolar affective disorder in chromosomal region 8q24. 01/04/2004 - 31/12/2006

          Abstract

          The proposed project uses a systematic SNP-based linkage disequilibrium (LD) approach to idenbfy a gene involved in susceptibility to BPAD located in a candidate regon on chromosome 8q24. The region has a size of about 30 cM now, but will first be narrowed down by fine mapping with dense microsatellite markers. Following this, SNPs from known genes in the region, preferably coding SNPs representing missense changes, will be used for searching LD. If this does not lead to the identification of LD, the approach will be extended to a systematic "initial screen" for LD using SNPs at a 20 kb spacing. This approach offers a high chance of detecting LD down to a size of about 10 kb, which is conservative against the background of empirical studies that have reported average LD distances of 30-300 kb in outbred populations (Huttley et al. 1999, Abecasis et al. 2001). The three most sigrufrcant findings from the "initial screen" will then be followed up by a second, denser SNP analysis. The denser SNP map will include genotyping of SNPs with an average distance of 1 kb within a range of 30 kb to either side of the signzficant SNP. To deal with the high-throughput requirements of such an approach, we will use a new technology, which was specifically developed for SNP analysis (PyrosequencingTM technology) and which we have recently introduced in our laboratory. As an additional option we will envisage to use a DNA pooling strategy to reduce the amount of genotyping work. DNA pooling of up to 100 individuals in a single PCR reaction has been proven to yield reproducible results (Barcellos et al. 1997) and sigruficantly reduces the number of necessary PCR reactions up to a factor of 100. At the moment, pilot studies are being performed in our laboratory to confirm the observations of other research groups that report comparability of allele frequencies obtained from individual genotyping and from pooled samples. If these pilot studies also give satisfactory results in our hands, we will consider to use the DNA pooling strategy for the "initial screen" for LD instead of individual genotyping.

          Researcher(s)

          Research team(s)

          Molecular genetic analysis of Schizophrenia. 01/04/2004 - 31/12/2005

          Abstract

          The aim of the project is the identification of schizophrenia genes within chromosomal regions implicated by linkage analysis. To narrow down the chromosomal region of interest, one of the world's largest samples of patients with schizophrenia will be used to systematically search for LD. This will finally lead to the idenhfication of the causative gene variant(s). LD mapping in genetically complex disorders is a statistical problem, which requires high through-put techniques of SNP genotyping in a large number of affected individuals and controls. Because this technique rapidly exceeds the capacity of conventional genotyping efforts (e.g. RFLP analysis, SSCA analysis) with regard to time exposure, costs, and amount of required DNA, alternative methods for SNP genotyping, such as DNA pooling and Pyrosequencing are needed to make LD mapping feasible. DNA pooling of up to 100 individuals in a single PCR reaction has been proven to yield reproducible results (Barcellos et al. 1997) and significantly reduces the number of necessary PCR reactions (up to a factor of 100). SNP genotyping of the pools of PCR products will then be done by a Pyrosequencing apparatus which performs primer extension reactions and detects the allelic distribution of each SNP by a light-producing chemical reaction.

          Researcher(s)

          Research team(s)

          Formal and molecular genetic studies of bipolar affective disorder. 01/04/2004 - 31/12/2004

          Abstract

          Researcher(s)

          Research team(s)

          Identification of novel genes and disease mechanisms underlying idiopathic epilepsies. 01/01/2004 - 31/12/2007

          Abstract

          In this project we will continue the initiated genetic studies in patients/families with different epilepsy syndromes. This project is expected to contribute to the understanding of the genetic mechanisms operating in one of the most prevalent and most complex group of neurological disorders (Hauser et al. 1993). Epilepsies represent a highly clinically heterogeneous group with both genetically determined and acquired epilepsy syndromes. Most epilepsy syndromes are complex disorders resulting from the interaction of (multiple) genes and environmental factors (Berkovic et al. 1998). A genetic contribution has been suggested for about 40% of epilepsy patients. Recent genetic studies have indicated that several epilepsy syndromes result from mutations in ion channels: ADNFLE (autosomal dominant nocturnal frontal lobe epilepsy) is associated with mutations in CHRNA4 and CHRNB2, while mutations in KCNQ2 and KCNQ3 lead to BFNC (benign familial neonatal convulsions). In GEFS+ (generalized epilepsy with febrile seizures plus) mutations in SCN1B, SCN1A, SCN2A and GABRG2 have been reported. More recently, we described de novo mutations in SCN1A in patients with SMEI (severe myoclonic epilepsy of infancy or Dravet syndrome). In vitro assays based on the expression of mutated ion channels allow testing of anti-epileptic activity of newly synthesized compounds. Development of new anti-epileptic drugs is needed since though existing drugs are efficient, a substantial number of patients do not become seizure-free. Also, mutations in LGI1 were shown to cause partial epilepsy with auditory features and mutations in GABRA1 are associated with JME (juvenile myoclonic epilepsy). Biochemical and morphological changes that make previously normal brain epileptic (epileptogenesis) remain largely unknown. Insight in this mechanism might eventually lead to the development of protective therapies that prevent the development of acquired forms of epilepsy e.g. after a cranial trauma. The generation of animal models based on epilepsy genes will therefore be instrumental in studying epileptogenesis. Molecular genetic studies of epilepsy syndromes have successfully identified chromosomal loci and genes using a linkage mapping in multiplex families and analysis of positional candidate genes within the respective chromosomal regions. To date, 20 loci are known for different epilepsy syndromes (Kaneko et al. 2002). However, only 10 epilepsy genes have been identified to date. Also it has been recognized that the known loci/genes explain only a limited fraction of all genetically determined epilepsy syndromes, underlining once more the huge clinical and genetic heterogeneity of this group of neurological disorders. This is exemplified by our recent finding of 4 novel loci, each one being a private locus in 1 family.

          Researcher(s)

          Research team(s)

          VIB-Abnormal proteins in the pathogenesis of neurodegenerative disorders (APOPIS). 01/01/2004 - 31/12/2006

          Abstract

          Degenerative disorders of the nervous system including Alzheimer's, Parkinson's, Huntington's, motor neuron and prion diseases are among the most debilitating illnesses, putting an enormous strain on both social and health care budgets in Europe. As these diseases progress, all but the most primitive functions of the nervous system are lost due to the degeneration and subsequent death of nerve cells. Eventually patients die in a state of incapacitation. Only a small fraction of cases can be accounted for by gene mutations. Altogether, the underlying aetiologies are poorly understood. A hallmark common to these neurodegenerative disorders is the deposition of abnormal protein aggregates. There is currently no treatment available that can halt or prevent, let alone reverse nerve cell degeneration. The APOPIS project is designed to apply the unique information provided by sequencing of the human genome to further the understanding of and to develop treatments for these devastating diseases. By integrating Europe¿s leading research centres in clinical research, human genetics, cell biology, genomics, proteomics and bioinformatics, the VERUM Foundation has devised a consortium to identify genes involved, determine their biological functions, establish their role in the pathophysiological processes and identify novel avenues for early diagnosis, treatment and prevention. The chosen approach is based on human population genetics complemented by the identification of modifier genes in model organisms that express both wildtype and mutant variants of known disease-related genes. The consortium meets the prerequisites for such a project: ground breaking research in functional genomics related to human health, creating synergies with and between national research efforts, teaming up with both small biotechnology and pharmaceutical companies for the development of diagnostic tools and new drugs, and providing training and mobility to improve the skills of young researchers.

          Researcher(s)

          Research team(s)

          Supercomputing cluster. 01/01/2004 - 31/12/2006

          Abstract

          Researcher(s)

          Research team(s)

            Abnormal proteins in the pathogenesis of Neurodegenerative disorders. 01/01/2004 - 31/12/2006

            Abstract

            Degenerative disorders of the nervous system including Alzheimer's, Parkinson's, Huntington's, motor neuron and prion diseases are among the most debilitating illnesses, putting an enormous strain on both social and health care budgets in Europe. As these diseases progress, all but the most primitive functions of the nervous system are lost due to the degeneration and subsequent death of nerve cells. Eventually patients die in a state of incapacitation. Only a small fraction of cases can be accounted for by gene mutations. Altogether, the underlying aetiologies are poorly understood. A hallmark common to these neurodegenerative disorders is the deposition of abnormal protein aggregates. There is currently no treatment available that can halt or prevent, let alone reverse nerve cell degeneration. The APOPIS project is designed to apply the unique information provided by sequencing of the human genome to further the understanding of and to develop treatments for these devastating diseases. By integrating Europe¿s leading research centres in clinical research, human genetics, cell biology, genomics, proteomics and bioinformatics, the VERUM Foundation has devised a consortium to identify genes involved, determine their biological functions, establish their role in the pathophysiological processes and identify novel avenues for early diagnosis, treatment and prevention. The chosen approach is based on human population genetics complemented by the identification of modifier genes in model organisms that express both wildtype and mutant variants of known disease-related genes. The consortium meets the prerequisites for such a project: ground breaking research in functional genomics related to human health, creating synergies with and between national research efforts, teaming up with both small biotechnology and pharmaceutical companies for the development of diagnostic tools and new drugs, and providing training and mobility to improve the skills of young researchers.

            Researcher(s)

            Research team(s)

            Identification of a gene for bipolar affective disorder in chromosomal region 8q24. 01/01/2004 - 31/12/2005

            Abstract

            Bipolar affective disorder (BPAD), also known as manic depressive illness, is characterized by severe aberrant mood swings in alternating periods of mania and depression. The disorder is common with a lifetime prevalence of about 1% in all human populations and results in high costs in terms of morbidity as well as mortality. BPAD is substantially responsive to drug treatment, but episodes tend to recur throughout life. Although the etiology and pathophysiology is widely unknown, family, twin and adoption studies argue for a strong genetic determination of the disease. Theories concerning the possible involvement of multiple genes of small effect and/or the occurrence of major allelic effects in epistasis have been advanced. In order to identify chromosomal loci harbouring genes that predispose to BPAD, in the absence of substantial molecular pathophysiological knowledge, linkage analysis is one of the best available methods. However, despite encouraging linkage findings by several research groups worldwide, no gene has yet been identified in BPAD. The linked regions usually cover large genetic distances (>10cM) that are prohibitive to systematic investigation of candidate genes. Nevertheless, gene identification has been shown to be possible in other diseases with complex inheritance (Diabetes mellitus type 2; Morbus Crohn) via the detection of linkage diseqiulibrium (LD) which exists over short genetic distances (<1cM). Until very recently, the search for LD in candidate regions was severely hampered by the lack of densely spaced markers (SNPs and microsatellites), physical maps, large patient samples, and sufficiently rapid, cheap, and accurate methods of genotyping SNPs. Many of these problems have been substantially reduced by the data provided by the Human Genome Project as well as development of high-throughput genotyping technologies. Our project builds on findings from a genome scan for linkage to BPAD that we recently finished. It will focus on the search for LD in a linked chromosomal region on 8q24 and finally the identification of the gene involved in the development of BPAD. The identification of a disease-related gene should allow to understand the nature of the corresponding gene products and their disease-related deviations. The obtained insights into the etiology of BPAD will open a corridor for new diagnostic and therapeutic options.

            Researcher(s)

            Research team(s)

            Molecular genetic analysis of neurodegenerative brain diseases. 01/10/2003 - 30/09/2006

            Abstract

            Researcher(s)

            Research team(s)

            Molecular genetic analysis of epilepsy syndromes. 01/10/2003 - 30/09/2005

            Abstract

            Epilepsy is a very frequent neurological disorder with a prevalence of 0.5% in western populations. Epilepsy is a very heterogeneous group of disorders. Genetics factors play an important role in some of the epilepsy variants. So far more than 20 genetic loci have been mapped and several genes have been identified in which mutations cause epilepsy. The aims of this project are to map novel loci for epilepsy. Subsequently the genes involved are identified. We are also performing mutation analyses of the known genes in patients with distinct epilepsy syndromes in order to make genotype-phenotype.

            Researcher(s)

            Research team(s)

            Identification of novel genes for dementia. 01/10/2003 - 30/09/2005

            Abstract

            Although dementia, fourth cause of death in the western countries, is a typical disease in older aged people, forms of this disease occuring at an earlier age also exist. These usually have a familial character, sometimes with autosomal dominant inheritance. Although dementia genes are known, the genetic cause in about 80% of dementia families remains unknown. In these families new dementia genes will be sought, which is relevant for understanding the biology of dementia in general.

            Researcher(s)

            Research team(s)

            A new mouse model for Alzheimer's disease : diffuse and truncated amyloïd ß42 pathology. 01/10/2003 - 30/09/2004

            Abstract

            Most cases of neurodegenerative brain diseases like Alzheimer's Disease (AD) or Parkinson's disease (PD) appear sporadically, whereas familial cases are rare. The genetic factors involved are, for example, APP- and presenilin genes in AD and a-synuclein and parkin genes in PD. Mutations in these genes will be studied in vitro, by cell culture experiments, as well as in vivo, in transgenic mouse models. It is expected that these studies will allow us to improve our understanding of the pathogenic mechanisms of the genetic as well as the sporadic forms of these diseases.

            Researcher(s)

            Research team(s)

            Sequence determination and annotation of a non-repetitive region on human chromosome 21p. 01/03/2003 - 28/02/2005

            Abstract

            Human chromosome 21 contains more than 20 disease genes. Although in most patients with Down syndrome the disease is caused by trisomy of chromosome 21 including 21p, most attention has been given to genes located on 21q. The short arm of chromosome 21 was not included in the human genome project because it is rich in repetitive sequences; however, recently it was shown that genes might be located within these repetitive sequences. We will determine the DNA sequence of chromosome 21p and we will analyze it for the presence of genes and polymorphic markers. We will thus substantially contribute to the completion of the human genome sequence and the understanding of human disorders including Down syndrome.

            Researcher(s)

            Research team(s)

            Identification and characterisation of genetic factors contributing to neurodegenerative brain diseases. 01/01/2003 - 31/12/2006

            Abstract

            Researcher(s)

            Research team(s)

            Identification an characterization of susceptibility genes for bipolar affective disorder. 01/01/2003 - 31/12/2006

            Abstract

            Our project builds on findings from four independent genome-wide linkage scans for bipolar affective disorder that have identified several chromosomal loci that may harbour genes for this disorder. The availability of large patient samples and the use of high-throughput genotyping methods will allow searching for linkage disequilibrium in the most promising regions and finally the identification of disease-associated genes.

            Researcher(s)

            Research team(s)

            Molecular genetics of idiopathic epilepsies. 01/01/2003 - 31/12/2004

            Abstract

            Epilepsy is one of the most common neurologic disorders, with a cumulative life-time incidence of about 3%. The epilepsies can be classified according to their etiology. For the idiopathic epilepsies there is no underlying cause other than a possible hereditary predisposition. Molecular genetic research has already identified thirteen genes in which mutations cause epilepsy. The fact that mutations in these genes are only found in a limited part of the families indicates that the idiopathic epilepsies are genetic heterogeneous. Therefore, further research towards new genes involved in these epilepsies is essential. The main purpose of this project is the identification of new loci and genes in which mutations cause an epileptic phenotype. Initially large multiplex families are studied. In these families the responsible genetic locus is identified by linkage analysis and the candidate genes in the region are screened for disease-related mutations. For nuclear families or isolated patients we use a candidate gene approach. The selection of the candidate genes is based on their homology with genes identified in epileptic phenotypes of man and mouse. Also known epilepsy genes are analyzed in families with a similar phenotype, which gives an indication of the frequency of mutations in that gene. This allows us to make genotype-phenotype correlations. By extending the mutation analysis to other epileptic phenotypes we investigate whether mutations in the gene cause other types of epilepsy or if they act like susceptibility factors. We will also investigate the functional effects of the identified mutations in in vitro and in vivo systems. Electrophysiological experiments are used to analyze mutations in subunits of ion channels. Mouse models will help to reveal the effect of the mutation on neuronal circuits or an entire organism.

            Researcher(s)

            Research team(s)

            Study of the molecular pathology of inherited peripheral neuropathies and related disorders. (A. JORDANOVA, Bulgarije) 16/11/2002 - 15/11/2003

            Abstract

            The research fellowship of Dr. Albena Jordanova, PhD, relates to the ending IUAP programme P4/17 on "Genetics of normal and abnormal differentiation (Genetica van normale en abnormale differentiatie)", in which Prof. Dr. C. Van Broeckhoven, head of the Molecular Genetics Laboratory at the University of Antwerp (UIA) is a sattelite group. This fellowship also fits into the new IUAP programme on "Molecular Genetics and Cell Biology (Moleculaire Genetica en Celbiologie)" submitted by Prof. Dr. C. Van Broeckhoven, project manager, to the University of Antwerp (UA) and DWTC in 2001. Prof. Dr. Peter De Jonghe and Prof. Dr. Vincent Timmerman are members of the steering group and responsible for the section on inherited peripheral neuropathies. Here we aim to contribute to the understanding of degeneration processes in the peripheral nervous system based on genes identified for inherited peripheral neuropathies, i.e. Charcot-Marie-Tooth disease and related disorders. Knowledge of the normal and dysfunction of these genes are expected to learn us the interaction processes of their gene products in myelin formation and maintenance.

            Researcher(s)

            Research team(s)

            VIB-Identification of novel genes for Alzheimer dementia and related disorders. 01/11/2002 - 31/10/2004

            Abstract

            Our main objective is to identify novel causal and risk genes for Alzheimer disease (AD) and related disorders. It can be expected that knowledge of these novel genes and their gene products will lead to major biological findings as was the case for the currently known causal AD genes: the amyloid precursor protein gene (APP), presenilin 1 gene (PSEN1) and presenilin 2 gene (PSEN2), and risk gene: apolipoprotein E gene (APOE) that together explain 20% of all AD cases in our Dutch population based sample. In addition, novel genes will help understanding all aspects of AD pathology in such that novel and more efficient therapeutic strategies can be developed. Our specific aims are to identify causal genes by linkage analysis studies in families not explained by mutations in the known genes APP, PSEN1 and PSEN2, to identify novel risk factors in a well characterized population-based and a hospital-based case/control sample of presenile AD and to determine their relative contribution to AD in general by analyzing the risk genes in a population-based sample of senile AD. The data obtained in the case/control samples will also be analyzed for gene-gene and gene-environment interactions. We will also examine genotype-phenotype correlations of novel mutations in known and novel AD genes using biological materials of mutation carriers such as plasma, lymphoblasts, fibroblasts and brains. We have access to 8 autosomal dominant presenile AD families without mutations in the known AD genes from a Dutch population-based study of presenile AD. Two families 1083 and 1270 were on their own powerful enough to generate conclusive LOD-scores, and we performed a genome-wide scan. The genome-wide scan in 1083 resulted in a locus at chromosome 17q21 showing conclusive linkage. Extended linkage and segregation analyses defined a candidate region of 4.8 cM. The microtubule associated protein tau gene (MAPT) is located in the candidate region; however, we excluded MAPT mutations in this family. Also, brain pathology did not reveal tau positive depositions. In the genome-wide scan of family 1270, conclusive LOD-scores were not reached. We will use a denser simple tandem repeat (STR) marker panel to improve linkage findings. In addition, we will collect novel families starting from presenile dementia patients with positive family history and negative for mutations in APP, PSEN1, PSEN2, MAPT and the prion protein gene (PRNP). Patients are ascertained through our genetic diagnostic unit and a Belgian memory clinic. A genome-wide scan will be performed and positional candidate genes will be identified in the linked regions using available and in-house developed bioinformatics tools. Candidate genes will be analyzed for mutations segregating with the disease in the pedigrees. We will analyze mutations in novel genes with respect to app metabolism and Aß secretion, specifically using cellular models expressing the mutated genes. We will examine Aß distribution in brain and/or plasma of mutation carriers. We will identify novel risk genes by analyzing in the presenile AD case/control samples functional candidate genes encoding proteins involved in known biological processes underlying AD pathology or proteins associated with known AD proteins. In this study, we will use single nucleotide polymorphisms (SNPs) covering the entire candidate region. We will also replicate positive data in a Dutch population-based senile AD case/control sample. We will statistically analyze the data to determine the effect on increased risk for AD. We will evaluate increased risk in relation to available data on genetic and environmental risk factors with respect to development and prognosis of AD.

            Researcher(s)

            Research team(s)

            Development of Environmental Diagnostics based on Toxicogenomics and Bio-informatics. 01/10/2002 - 30/09/2006

            Abstract

            In the present proposal, different emerging technologies will be applied and integrated to create innovative, sensitive and discriminating technologies for environmental toxicity assessments: DNA array technology and bio-informatics. The global objective of the present proposal is to develop an expert system linked to a bio-informatics platform that can distinguish the mode of action of chemicals based on the gene expression profile it induces within in vitro cell systems. This model will be developed in two steps: we will first start to evaluate the potential to classify the toxic effects of a group of highly (structurally) diverse environmental contaminants representing the major toxicological modes of action. Using the gene expression profiles, measured using micro-arrays, we will construct a bio-informatics classifier as an expert model. This model will then be assessed on its robustness (how does the system recognize known molecules?), its correctness (how are chemicals with the same mode of action classified?) and its discriminatory power (how good can theoretically distinct modes of actions be recognised?) Once the initial version of the model works we will, in a second tiered step, further refine the classifier by studying chemicals with a defined mode of action: endocrine disrupting chemicals. Testing these highly similar working chemicals displaying more structural similarity on the in vitro system will be the ultimate challenge to explore the full potential of this promising technology.

            Researcher(s)

            Research team(s)

            Identification of novel genes for early-onset dementia. 01/10/2002 - 30/09/2004

            Abstract

            Gelieve aan te vullen a.u.b.

            Researcher(s)

            Research team(s)

            Identification of biomarkers for bipolar disorder by means of suppressive subtraction hyhridisation. 01/10/2002 - 30/09/2004

            Abstract

            Bipolar disorder (BP) is a severe psychiatric condition characterised by periods of mania and depression. The infliction is devastating for patient and his surroundings, on average 10 to 20% of the patients untimely die by suicide. BP has a lifetime prevalence of 0,5 ' 1,5%. Family, twin and adoption studies have shown that BP has a significant genetic component. Several linkage and association studies identified candidate susceptibility genes and candidate loci but till now none of these yielded a true disease-causing gene. The real problem of this disorder lies within the treatment. The evaluation period for subscribed medicines for a depressive period is 4 to 6 weeks, after witch another treatment can be tested when the previous one has proven to be ineffective. In 20% of the cases no effective treatment can be found within 2 ' 3 years. Moreover the effectiveness of mood stabilizing treatment such as the treatment with lithium, carbamazepine or valproate can only be evaluated when proven ineffective, when a patient refalls into an affective disordered condition. The goals of the proposed research is to discover biomarkers for BP, which can be used to determine differences in gene expression profiles between patients and controls. Subsequently these biomarkers will be used to determine a difference between the various subtypes of the disease, and between the different affective periods of the disease. These biomarkers will be obtained by a `Suppression Subtractive Hybridisation' (SSH) of post mortal hippocampal, frontal lobe tissue, whole blood and lymphoblast cells. The analyses of these subtracted libraries will result in a list of differential expressed genes between patients and controls. With this information answers will be sought for questions like: which genes participate in the disease pathways, what are the gene expression differences between patient and control, what are the gene expression differences between the various subtypes and different affective periods of the disorder, which connections can be made between gene expression and the different genes and what are the parallels between the expression in brain and in blood?

            Researcher(s)

            Research team(s)

            Molecular genetics and cell biology. 01/01/2002 - 31/12/2006

            Abstract

            This network proposal has as major theme the molecular genetics and cell biology of human inherited disorders. This network groups 11 excellent research laboratories at the University of Antwerp active in molecular genetics of diseases such as Alzheimer dementia, psychiatric disorders, mental retardation, peripheral neuropathies, hearing impairment and bone disorders. The availability of the human genome sequence will not only provide the molecular geneticists new tools to accelerate their research topics (such as bioinformatics, SNPs, etc.), but also lead to functional studies of the respective disease causing genes. The post-genome era will therefore need the integration of high-throughput techniques and bio-informatics, but also collaboration with excellent cell biology laboratories in the network located at other Belgian universities.

            Researcher(s)

            Research team(s)

            Institutional funds VIB8: Department of Molecular Genetics. 01/01/2002 - 31/12/2006

            Abstract

            The department of Molecular Genetics is specialized in the genetic analysis of complex neurological and neuropsychiatric diseases. All these diseases are multifactorial in nature i.e. they are expressed due to the interplay of genes and environment. In some of these diseases the inheritance pattern is mainly mendelian (e.g. CMT) with gene defects in single genes. In others only in a small fraction of patients genetic factors are apparent. In the latter cases, several families with mendelian inheritance have been identified (= monogenic component). In the majority of the cases the disease expression is modulated by complex gene-gene and gene-environment interactions. Our major aims are to identify novel molecular mechanisms for disease causation and effective drug treatment for these devastating diseases. We use different genetic approaches to identify genes (causal mutations) and genetic risk factors (predisposing polymorphisms) based on molecular genetic and genetic epidemiology approaches. The contribution of a disease gene is estimated in population and hospital based patient series. Also, we will examine these genes and risk factors in relation to other genes as well as to environmental risk factors. We model mutations or polymorphisms in cellular systems (e.g. stable cDNA transfectants) and mouse animal models. These systems allow us to understand the effect of mutations/polymorphisms on the normal functioning of the actual gene product. Also, the observed biological phenomena can be compared directly with those observed in patients. Finally, these models should allow us to test for treatment approaches.

            Researcher(s)

            Research team(s)

            Gene therapy: from gene transfer to clinical applications 01/01/2002 - 31/12/2006

            Abstract

            This FWO scientific research network on gene therapy brings flemish (and belgian) laboratories active in the field of gene therapy together in order to stimulate the interaction, to exploit the complementarity of knowledge and technology between the participating partners, and to be able to compete with foreign research groups in the field. Research programs will be focused on both fundamental and clinical aspects of gene therapy.

            Researcher(s)

            Research team(s)

            Identification of genes for affective disorders : a family based approach. 01/01/2002 - 31/12/2005

            Abstract

            The laboratory of Molecular Genetics, University of Anwerp (UIA), initiated its research into the genetics of affective disorders aiming at identifying genes for bipolar disorder (BP) and recurrent unipolar (UP) disorder in 1989, a time when it was not so evident that, taken the available methodology and the complexity ofthe disorders, genes could be fo.und. Over the years different approaches were folIowed in our laboratory that included 1) positional cloning in multiplex families, 2) association studies of functional candidate genes in case/control samples, 3) development of new technologies to identify genes associated with triplet repeat expansions, and 4) genetic analysis of temperament dimensions as predisposing factors for affective disorders (see CV ofprincipal investigator). Although progress was made over the years it is important to recognise that no major breakthroughs were realised: as for to date neither us nor anyone else in the field of psychiatric genetics has identified a major gene for affective disorders or any other psychiatric disorder such as for example schizophrenia. It is therefore important that lessons are leamed from mistakes made in the past and that new opportunities offered by the large collections ofwell defined patient materials gathered over the years, and of new methodologies and technologies available today, are optimally exploited in order to guarantee results in the near future.

            Researcher(s)

            Research team(s)

            Understanding neurological diseases : a molecular genetic approach. 01/01/2002 - 31/12/2004

            Abstract

            We aim to identify novel genes for Alzheimer Disease (AD), Epilepsy and Charcot-Marie-Tooth (CMT) neuropathy using multiple molecular genetic approaches. Causative genes will be identified using genome-wide scans in informative families that are not explained by mutations in known genes. Genotype/phenotype correlations are made using clinical, neurophysiological and neuropathological data. In vitro studies will be performed with novel mutations in known or newly identified genes. Efforts will be made to construct transgenic mouse models making use either of constructs containing mutations leading to an extremely severe phenotype and/or multiple transgene models. The identification of genes causing neurological diseases is the first step towards a better understanding of fundamental biological processes operating in the central and peripheral nervous system.

            Researcher(s)

            Research team(s)

            Allowance for research equipment : BIOMEK FX liquid handling system. 01/01/2002 - 31/12/2002

            Abstract

            The BIOMEK FX is designed for high throughput processing of samples for molecular biological techniques such as : PCR reaction assembly; sequencing set-up and purification, plasmid isolation; set-up of genotyping reactions; streptavidin/biotine based separation techniques; reformatting of 96 and 384 wells plates.

            Researcher(s)

            Research team(s)

              Analysis of variable gene expression aetiology of complex brain diseases. 01/10/2001 - 30/09/2004

              Abstract

              Complex diseases often represent a group of clinically similar conditions with heterogeneous aetiologies due to an interplay of genetic and environmental factors. Multiple studies have demonstrated that independent of causal mutations, variations in regulatory regions leading to variable gene expression of functional candidate genes, can be key determinants of disease development. Our first objective is therefore, a systematic screening for polymorphisms associated with increased disease risk in the regulatory regions of candidate genes for Alzheimer dementia (AD) and other complex disorders like bipolar disorder (BP). Consequently, the effect of these promoter variations on transcriptional regulation will be studied using luciferase reporter gene analyses and the factors involved in allele-specific expression characterised using electrophoretic mobility shift assays (EMSA), DNaseI footprinting (DF), database searches and comparative sequence analysis in different species. The functionality of the candidate binding proteins will be tested by competitive EMSA en DF experiments. Interference and protection assays as well as systematic mutation analysis will provide further information on the nucleotides involved in DNA-protein interaction. When an unknown protein binds the target elemënt,` the gene encoding this protein will be cloned by purification of the protein followed by mass spectrometry and sequencing, database searches, in vitro expression library screening or mammalian expression cloning. Currently, we are analysing the EGAD-related PSENI promoter variations using the strategy described above. When optimised and proven to be successful for the analysis of the PSENI promoter, this strategy will be applied to characterise differential transcription effects in other AD genes and candidate genes for other complex diseases like BP.

              Researcher(s)

              Research team(s)

              Molecular genetic analysis of personality in relation to complex multifactorial psychiatric disorders: bipolar disease and major depression. 01/10/2001 - 29/02/2004

              Abstract

              The investigation of normal personality is a new approach to study psychiatric disorders. Recently it was demonstrated that personality disorders represent the extreme of a continuum of normally distributed personality traits. Further it was shown that the interaction between different aspects of personality could increase the risk of a depression. With regard to the field of psychiatric genetics, this is of major importance. The study of normal personality traits can inform us about risk genes for psychiatric disorders, like manic-depressive psychosis. Advantages of working with normal traits are the possibility to screen large populations and the more accurate phenotype. In our study, a North Swedish population of 2400 healthy volunteers was screened using a personality questionnaire. The extremely high and low scoring individuals are selected for genotyping of candidate genes from the dopaminergic, serotonergic and hormonal pathways. Genes that show a positive association with a personality trait will be tested on a population of depressive patients and controls.

              Researcher(s)

              Research team(s)

              Molecular genetic analysis of epilepsy syndromes. 01/10/2001 - 30/09/2003

              Abstract

              Epilepsy is a very frequent neurological disorder with a prevalence of 0.5% in western populations. Epilepsy is a very heterogeneous group of disorders. Genetics factors play an important role in some of the epilepsy variants. So far more than 20 genetic loci have been mapped and several genes have been identified in which mutations cause epilepsy. The aims of this project are to map novel loci for epilepsy. Subsequently the genes involved are identified. We are also performing mutation analyses of the known genes in patients with distinct epilepsy syndromes in order to make genotype-phenotype correlations.

              Researcher(s)

              Research team(s)

                Identification and characterization of genes involved in neurodegenerative dementias. 01/10/2001 - 31/12/2002

                Abstract

                The aim of this project is the identification of genetic variations that contribute to both pathologic (dementia) and normal (memory) cognitive phenotypes. The underlying idea is that inheritable factors that determine normal memory performance, are also at the basis of dementia phenotypes. In this study we try to gain insight in the genetic component of dementia, especially Alzheimer's disease, via this alternative route of normal phenotypes. For both phenotypes large scaled epidemiologic populations from the Netherlands and Sweden are used.

                Researcher(s)

                Research team(s)

                  Etiology of spinocerebellar ataxia type 7 using cellular and animal models: correlation to neuropathology. 01/01/2001 - 31/12/2004

                  Abstract

                  Here we aim at understanding the dysfunction of ataxin-7 in relation to SCA7 pathophysiology using in situ (e.g. patient autopsy tissues), in vitro (e.g. cellular models) and in vivo (e.g. transgenic mice) studies. 1) In situ studies: relationship to neuropathology: We will analyse the correlation between disease severity, its neuropathology and number of nuclear inclusions observed in affected tissues, 2) In vitro studies: cellular models: We will generate cellular models by transient transfection of neuronal and nonneuronal cell lines with a tagged SCA7 cDNA, 3) In vivo studies: transgenic mice:Two different transgenic mouse models will be generated using either a large insert genomic construct or an ataxin-7 cDNA construct.

                  Researcher(s)

                  Research team(s)

                  Molecular cell biology and genetics of memory and learning processes.(Sabbatical/FWO) 01/01/2001 - 31/12/2001

                  Abstract

                  Recent studies have contributed to our understanding of the cellular and molecular basis of memory, both short term (transient) and long term (permanent) memory. Molecular biology techniques allowed to study the process of memory at the molecular level using inducible and conditional targetting in mice so that a protein involved in the memory and learning process was inactivated or induced during or just after the learning process in mice. The aim of the project is to obtain a profound knowledge of molecular cell biology and genetics of memory and learning and the instruments used to analyse these processes in the research laboratory of Mark Mayford, SCRIPPS, San Diego (La Jolla). This knowledge will be translated to the molecular genetics research of normal memory, benigh forgetfulness and dementia in human, on-going in the Laboratory of Molecular Genetics, UIA

                  Researcher(s)

                  Research team(s)

                    Molecular cell biology and genetics of memory and learning processes.(Sabbatical BOF/UIA) 01/01/2001 - 31/12/2001

                    Abstract

                    Recent studies have contributed to our understanding of the cellular and molecular basis of memory, both short term (transient) and long term (permanent) memory. Molecular biology techniques allowed to study the process of memory at the molecular level using inducible and conditional targetting in mice so that a protein involved in the memory and learning process was inactivated or induced during or just after the learning process in mice. The aim of the project is to obtain a profound knowledge of molecular cell biology and genetics of memory and learning and the instruments used to analyse these processes in the research laboratory of Mark Mayford, SCRIPPS, San Diego (La Jolla). This knowledge will be translated to the molecular genetics research of normal memory, benigh forgetfulness and dementia in human, on-going in the Laboratory of Molecular Genetics, UIA

                    Researcher(s)

                    Research team(s)

                      VIB-Identification of novel genes for AD : a population based approach. 01/11/2000 - 31/10/2002

                      Abstract

                      Researcher(s)

                      Research team(s)

                        VIB-Genetic and phenotypical analysis of Alzheimer's disease. 01/11/2000 - 31/10/2001

                        Abstract

                        Our main objective is to identify novel causal and risk genes for Alzheimer disease (AD). It can be expected that knowledge of these novel genes and their gene products will lead to major biological findings as was the case for the currently known causal AD genes: amyloid precursor protein gene (APP), presenilin 1 gene (PSEN1) and presenilin 2 gene (PSEN2), and risk gene: apolipoprotein E gene (APOE). The known genes explain at the maximum 20% of all AD cases. Also, they will help understanding all aspects of AD pathology in such that novel and more efficient therapeutic strategies can be developed. Our specific aims are to identify causal genes by linkage analysis studies in families not explained by mutations in the known genes APP, PSEN1 and PSEN2, to identify novel risk factors in a well characterized defined population based case/control sample of presenile AD and to determine their relative contribution to AD in general by analyzing the risk genes in a population based sample of senile AD. The data obtained in the population based samples will also be analyzed for gene-gene interactions and gene-environment interactions. We will also examine genotype-phenotype correlations of novel mutations in known AD genes or mutations in novel AD genes using biological materials of mutation carriers such as plasma, cell lines and brains. To identify the novel causal genes we will perform a high density genome wide screen in 8 families consistent with autosomal dominant inheritance of AD. Positional candidate genes will be identified and analyzed for mutations and segregation in the pedigrees. Mutations in novel genes will be analyzed in respect to APP metabolism and Aß secretion specifically using cellular models expressing the mutated genes. Aß distribution will also be examined in brain of mutation carriers. Novel risk genes will be identified by analyzing in the population based presenile AD cases/controls functional candidate genes coding for proteins involved in known biological processes underlying AD pathology, proteins associated with known AD proteins or coding for the regulatory regions of the known AD genes. In this study we will use single nucleotide polymorphisms (SNPs) covering the entire candidate region. Positive data will also be replicated in the population based senile AD case/control sample. Data will be statistically analyzed to determine the effect on increased risk for AD. Increased risk will be evaluated in respect to available data in the samples on risk and environmental risk factors with respect to development and prognosis of AD.

                        Researcher(s)

                        Research team(s)

                          Molecular genetic analysis of Alzheimer dementie. 01/10/2000 - 30/09/2003

                          Abstract

                          Currently, 3 genes are identified that, when mutated, cause presenile Alzheimer dementie (AD). Senile AD is at least partly caused by genetic factors. However, the currently known causal AD genes and genetic risk factors cannot explain all AD cases. The aim of this project is to identify new causative genes in autosomal dominant AD families, and genetic risk and protection factors in complex familial and non-familial forms of AD.

                          Researcher(s)

                          Research team(s)

                            Genome-wide search for genes that are involved in Alzheimer's disease. 01/10/2000 - 30/09/2002

                            Abstract

                            Alzheimer's disease (AD) is the most frequent form of senile dementia and the most common cause of death in western societies. AD is at least in part caused by genetic factors and in some cases AD segregates as a monogenic, autosomal dominant trait in families. In 18 to 50% of these monogenic cases, mutations have been identified in the ß-amyloid precursor protein gene (APP), the presenilin-1 (PSEN1) and the presenilin-2 (PSEN2) genes. The aim of this project is to identify new genes in which mutations are responsible for autosomal dominant AD using a positional cloning strategy.

                            Researcher(s)

                            Research team(s)

                              Gene environment interaction in Parkinson's disease. 01/10/2000 - 30/09/2001

                              Abstract

                              Parkinson's disease is probably caused by a neurotoxic influence on a vulnerable substantia nigra. Our investigation involves the detection of risk factors for the disease.

                              Researcher(s)

                              Research team(s)

                                Transgenesis for the functional analysis of eukaryotic genes 01/01/2000 - 31/12/2003

                                Abstract

                                The aim of the project is to establish a centralised facility for transgenesis within the University of Antwerp. This facility will be responsible for the transgenesis and gene targeting of ES cells, the generation of animal models and the in vitro culture work of genetically modified non-differentiated cells ( ES cells) and differentiated cells. The transgene technology will be applied in the functional studies of: Genes involved in osteo/chondrogenic differentiation (Ecm1,Itm2a); Genes involved in the pathogenesis of affective disorders; Genes coding for voltage-gated K+ channels .

                                Researcher(s)

                                Research team(s)

                                  Identification of genes and genetic factors that play a role in epilepsy. 01/01/2000 - 31/12/2003

                                  Abstract

                                  The hypothesis that genetic factors play an important role in some epilepsy variants has recently been endorsed by the identification of large pedigrees with multiple affected members. In several large families, molecular genetic studies have mapped the disease locus within the human genome. At present, approximately twenty epilepsy loci have been localized and the underlying gene defect has been found in four variants. De identification of the other gene defects will be instrumental in the study of the pathophysiology of seizures and epileptogenesis. The construction of new cellular models and transgenic animals will provide new tool to study existent and newly developed anti-epileptic drugs.

                                  Researcher(s)

                                  Research team(s)

                                  Study of (de) (re) generation processes in peripheral nervous system based on inherited neuropathies. 01/01/2000 - 31/12/2000

                                  Abstract

                                  The Charcot-Marie-Tooth (CMT) disease is one of the most frequent hereditary neuromuscular disorders. Patients sometimes become severely disabled even at a very young age. There is currently no effective treatment for this disease. It is characterised by genetic heterogeneity, and understanding of genetic basis of different genetic variants is important for diagnosis and developing of adequate therapy. It seems probable that information about new CMT genes could promote genetic investigations of other neurological disorders. Usually CMT is subdivided into two groups. CMT1 is characterised by remarkably decreased nerve conduction velocities and caused by alterations of myelin structure. The main genes responsible for CMT1 are already known. The axonal type of CMT, referred as CMT2 is less investigated. Although several CMT2 loci have been assigned, the corresponding genes have not yet been identified. Two large CMT2 families have been found in Russia and are clinically and electrophysiologically characterised. They are suitable for localisation of the corresponding genes with the aim to identify the disease causing genes.

                                  Researcher(s)

                                  Research team(s)

                                    Genetic, functional, clinical and anatomopathological research of inherited peripheral neuropathies. 06/12/1999 - 30/09/2002

                                    Abstract

                                    The inherited peripheral neuropathies belong to the most frequent neuromuscular diseases and occur in populations of different ethnic origin. Considerable genetic heterogeneity is present in hereditary motor and/or sensory neuropathies (HMSN, HMN and HSN), including Charcot-Marie-Tooth disease (CMT). This leads to considerable diagnostic problems in clinical practice. The expression of the disease phenotype is extremely variable and ranges from almost no symptoms to severe muscle wasting, atrophy and deformities of hands and feet. Some patients have, at an early stage of the disease, a severe handicap and may become wheelchair dependent. The identification of disease causing mutations in different genes will facilitate accurate diagnosis of patients with inherited peripheral neuropathies obviating the need for invasive diagnostic procedures, such as nerve biopsy. Genotype / phenotype correlations are essential for the selection of specific mutations of which the functional impact can be analyzed in cellular or transgenic animal models. In this project we aim to identify novel loci, genes and mutations responsible for different forms of inherited peripheral neuropathies and to contribute to the development of more effective treatments.

                                    Researcher(s)

                                    Research team(s)

                                      Detection, identification and classification of genes in de analysis of genome sequences 01/10/1999 - 30/09/2002

                                      Abstract

                                      The complete genome sequence of several species has been determined, and several other sequences are expected to follow. The main objective of this project is finding and classifying possible coding sequences (CDS) and the determination of their structure and/or function. The similarity between postulated coding sequences will be calculated using a variety of scoring methods. The scores will then be used to detect gene groups or families using tree construction and other classification methods. The database will be scanned for additional members of the families. Using alignments and other computer sequence analysis methods the structure and function of these families will be studied.

                                      Researcher(s)

                                      Research team(s)

                                        Molecular genetic analysis of personality in relation to complex multifactorial psychiatric disorders: bipolar disease and major depression. 01/10/1999 - 30/09/2001

                                        Abstract

                                        The investigation of normal personality is a new approach to study psychiatric disorders. Recently it was demonstrated that personality disorders represent the extreme of a continuum of normally distributed personality traits. Further it was shown that the interaction between different aspects of personality could increase the risk of a depression. With regard to the field of psychiatric genetics, this is of major importance. The study of normal personality traits can inform us about risk genes for psychiatric disorders, like manic-depressive psychosis. Advantages of working with normal traits are the possibility to screen large populations and the more accurate phenotype. In our study, a North Swedish population of 2400 healthy volunteers was screened using a personality questionnaire. The extremely high and low scoring individuals are selected for genotyping of candidate genes from the dopaminergic, serotonergic and hormonal pathways. Genes that show a positive association with a personality trait will be tested on a population of depressive patients and controls.

                                        Researcher(s)

                                        Research team(s)

                                          Molecular genetic analysis of complex pathologic and normal cognitive phenotypes. Identification of genetic variations involved in dementia and memory. 01/10/1999 - 30/09/2001

                                          Abstract

                                          The aim of this project is the identification of genetic variations that contribute to both pathologic (dementia) and normal (memory) cognitive phenotypes. The underlying idea is that inheritable factors that determine normal memory performance, are also at the basis of dementia phenotypes. In this study we try to gain insight in the genetic component of dementia, especially Alzheimer's disease, via this alternative route of normal phenotypes. For both phenotypes large scaled epidemiologic populations from the Netherlands and Sweden are used.

                                          Researcher(s)

                                          Research team(s)

                                            Cloning of genes containing expanded trinucleotide repeats in bipolar affective disorder. 01/10/1999 - 30/09/2001

                                            Abstract

                                            This project aims to clone genes with expanded triplet repeats. For this purpose one can start from total genomic DNA or from cloned sequences. Triplet repeats can be isolated from total genomic DNA by existing techniques (e.g. DIRECT) or by implementing new hybridisation-based techniques. Triplet repeats from cloned sequences will be isolated by screening cDNA libraries, regio specific genomic libraries and YACs with the corresponding triplet containing repeat oligonucleotides.

                                            Researcher(s)

                                            Research team(s)

                                              Cellular models for the study of biological (dys)function of genes, related to dementia and memory. 01/10/1999 - 28/02/2001

                                              Abstract

                                              This project aims at developing cellular model systems for dementia and memory. Therefore, wild type and mutant cDNAs derived from genes, involved in dementia and memory, will be introduced in (non)neuronal cell lines by means of transfection. Cell lines expressing WT or mutant cDNA will be compared with each other. A comparison with patient material will also be made in order to exclude artefacts due to the overexpression system. Such cellular model systems are needed to perform preliminary studies that will lead to a curative therapy for dementia as well as to study normal memory functions and mechanisms that underlay dementia.

                                              Researcher(s)

                                              Research team(s)

                                                Genome-wide search for genes that are involved in Alzheimer's disease. 01/10/1999 - 30/09/2000

                                                Abstract

                                                Alzheimer's disease (AD) is the most frequent form of senile dementia and the most common cause of death in western societies. AD is at least in part caused by genetic factors and in some cases AD segregates as a monogenic, autosomal dominant trait in families. In 18 to 50% of these monogenic cases, mutations have been identified in the ß-amyloid precursor protein gene (APP), the presenilin-1 (PSEN1) and the presenilin-2 (PSEN2) genes. The aim of this project is to identify new genes in which mutations are responsible for autosomal dominant AD using a positional cloning strategy.

                                                Researcher(s)

                                                Research team(s)

                                                  Identification of genes and genetic factors that play a role in Alzheimer dementia. 01/01/1999 - 31/12/2002

                                                  Abstract

                                                  In 40 to 60% of the Alzheimer disease (AD) patients, the disease has a genetic aetiology, in most cases involving multiple genes and environmental lectors. Three genes (APP, PSENI and PSEN2) and 1 genetic risk factor (APOE) are identified, and other risk factors are suggested. This project aims at further genetic analyses of AD. Additional AD genes will be identified by genetic linkage analyses in families with autosomal dominant AD. Risk genes will he identified by genetic association studies in populations of unrelated AD patients.

                                                  Researcher(s)

                                                  Research team(s)

                                                    VIB-A study of genetic factors in Creutzfeldt-Jakob disease. 01/01/1999 - 31/12/2001

                                                    Abstract

                                                    Genetic factors play an important role in the susceptibility of Creutzfeldt-Jakob disease (CJD), the most common spongiform encephalopathy in men. The prion protein gene (PRNP) has been shown to play a key role in the pathogenesis of spongiform encephalopathies in man and animals. PRNP has been implicated in familial, iatrogenic sporadic and new variant forms of CJD. In addition to PRNP, other genes may be implicated in the susceptibility to CJD, most likely in interaction with PRNP and/or non-genetic factors including nutrition and medical procedures. The general objective is to identify new genetic factors that are involved in the risk of and susceptibility to CJD.

                                                    Researcher(s)

                                                    Research team(s)

                                                      VIB-Multicentre clinical trial in post concussional syndrome and determine apoE4 in the blood of patients. 01/01/1999 - 31/12/2000

                                                      Abstract

                                                      A double blind, placebo controlled study to evaluate the efficacy and safety of piracetam administration in the prevention and treatment of post concussional syndrome (PCS) is performed. Also, the genetic predisposition to the APOE genotype to the development of PCS is studied.

                                                      Researcher(s)

                                                      Research team(s)

                                                        Efficiency of gene transfer in human dendritic cells and hematopoietic stem cells. 01/01/1999 - 31/12/2000

                                                        Abstract

                                                        The purpose of this research is to investigate the efficiency of gene transfer and gene expression in human hematopoietic cells by nonviral and viral transduction methods and study of factors influencing transduction efficiency in both gene transfer systems. The development of a dendritic cell based tumor vaccine is a potential consequence of this study.

                                                        Researcher(s)

                                                        Research team(s)

                                                          Hereditary Neuralgic Amyotrophy (HNA): Identification of the genetic defect by positional cloning. 01/01/1999 - 31/12/1999

                                                          Abstract

                                                          Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant recurrent focal neuropathy. HNA patients have episodes of painful brachial plexus neuropathy with muscle weakness and atrophy. Minor dysmorphic features can be present, but these do not always segregate with the disease phenotype. We described a large HNA family showing significant linkage to chromosome 17q24-q25 and defined a candidate region of 16 cM. Genetic analysis of 6 new HNA-families allowed us recently to narrow down the HNA-candidate region to a 9,3 cM interval between the flanking markers D17S785 and D17S836. A North American group defined a HNA-candidate region that overlaps our region and allows to construct a minimal HNA candidate region of 3,5 cM, between the markers D17S785 and D17S802. In addition we have excluded two candidate genes, a putative sialyltransferase and the SFRS2 splicing factor by direct DNA sequencing in our HNA-families. The aims of the proposed research project are: 1. the construction of a clone contig of the latest HNA-candidate region, 2. the mapping of positional and functional candidate genes on the clone contig, 3. the identification of new genes in the HNA-region, and 4. the mutation analysis of genes identified by 2. and 3. through direct DNA sequencing in members of our HNA-families, in order to identify the causative genetic defect.

                                                          Researcher(s)

                                                          Research team(s)

                                                            Molecular genetic analysis of complex pathologic and normal cognitive phenotypes. Identification of genetic variations involved in dementia and memory. 01/01/1999 - 30/09/1999

                                                            Abstract

                                                            The aim of this project is the identification of genetic variations that contribute to both pathologic (dementia) and normal (memory) cognitive phenotypes. The underlying idea is that inheritable factors that determine normal memory performance, are also at the basis of dementia phenotypes. In this study we try to gain insight in the genetic component of dementia, especially Alzheimer's disease, via this alternative route of normal phenotypes. For both phenotypes large scaled epidemiologic populations from the Netherlands and Sweden are used.

                                                            Researcher(s)

                                                            Research team(s)

                                                              Functional analysis of mutations in the peripheral myelin protein zero gene (PO) associated with Charcot-Marie-Tooth disease type 1. 01/10/1998 - 30/09/2002

                                                              Abstract

                                                              Charcot-Marie-Tooth disease type 1, a disorder of the peripheral nervous system, is genetically heterogeneous with loci on chromosomes 1, 17 and X. We identified different mutations in the PO gene on chromosome 1. The aim of this project is a functional analysis of P0 mutations. A first approach is in vitro analysis, in a later stage in vivo experiments will be performed. Knowledge about the pathogenesis of CMT1 can give us insights about the functioning of the peripheral nervous system. Insights in the pathogenesis of the disease are a first step towards the development of an effective therapy. Transgenic animals can act as a model for human neuropathies to test therapies.

                                                              Researcher(s)

                                                              Research team(s)

                                                                Molecular genetic analysis of the brachial plexus neuropathy (Hereditary Neuralgic Amyotrophy, HNA). 01/10/1998 - 30/09/2000

                                                                Abstract

                                                                HNA is a rare autosomal dominant neuropathy characterised by episodes of attacks of pain followed by muscle weakness and sensory disturbances due to brachial plexus neuritis. Recently, a genetic linkage study in two American HNA families suggested a HNA locus on chromosome 17q. Segregation analysis of STR markers in a Turkish pedigree refined the HNA locus to a 16 cM region on chromosome 17q24-25. In this IWETO research, we aim to identify the HNA gene / mutation. After refinement of the HNA locus we will construct a physical map of the minimal linkage region using yeast artificial chromosomes (YACs). The YAC-contig will be subcloned in sCOGH cosmids. After exontrapping or direct cDNA selection on this cosmid library, mutation analysis on the subtracted genes may lead to the identification of the HNA gene. This will lead to a better understanding of the HNA aetiology and related peripheral neuropathies and provide a DNA diagnosis for HNA patients and asymptomatic individuals.

                                                                Researcher(s)

                                                                Research team(s)

                                                                  In vitro study on the possible influence of presenilin mutations on tau phosphylation and cell death. 01/10/1998 - 30/09/2000

                                                                  Abstract

                                                                  Alzheimer's disease (AD) is a fatal, neurodegenerative disorder, characterised by a progressive dementia. In addition to the presence of extracellular senile plaques, AD is pathologically identified by the presence of intracellular neurofibrillary tangles in the brain. These neurofibrillary tangles are primarily composed of the microtubuli associated protein, tau, which appears in a hyperphosphorylated state. Recently, the presenilin-l (PS-1) and presenilin-2 (PS-2) gene were identified. When mutated these genes cause AD. The aim of this IWETO research project is to develop an in vitro model to study how PS-1/2 mutations can lead to AD pathogenesis. In this frame the possible influence of PS-1/2 mutations on tau phosphorylation will be studied. Intracellular Ca2+ concentrations will be measured in PS-1/2 cDNA transfected cells. Finally, we will examine whether apoptosis (programmed cell death occurs in PS-1/2 overexpressing cells.

                                                                  Researcher(s)

                                                                  Research team(s)

                                                                    Gene environment interaction in Parkinson's disease. 01/10/1998 - 30/09/2000

                                                                    Abstract

                                                                    Parkinson's disease is probably caused by a neurotoxic influence on a vulnerable substantia nigra. Our investigation involves the detection of risk factors for the disease.

                                                                    Researcher(s)

                                                                    Research team(s)

                                                                      Efficiency of gene therapy in human hematopoietic stem cells. 01/10/1998 - 30/09/2000

                                                                      Abstract

                                                                      The aim of this project is to investigate 1) in which stem cell populations gene transfer will lead to stable long term expression of the transfered genes in the different hematopoietic lineages (myeloid, T, B) and 2) which is the most efficient method of gene transfer (adeno-associated virus, liposomes, lipofectine) and which are the most efficient promotors to obtain stable long term expression of the transfered genes (CMV IE promotor, HSV-1 thymidine kinase promotor, c-kit promotor, CD34 promotor. Target cells for hematopoietic gene therapy will be CD34++ CD38- cells, which are known to very primitive cells, or subpopulations thereof. Culture assays used will be the pre-CFC assay and fetal thymus (SCID).

                                                                      Researcher(s)

                                                                      Research team(s)

                                                                        Identification of genes that increase the susceptibility to bipolar spectrum disorders. 01/10/1998 - 30/11/1998

                                                                        Abstract

                                                                        Our laboratory has a 10 year tradition in the research of bipolar spectrum disorders (BP). The aim of this project is thc identification of genes that increase the vulnerability to BP. Family- and population strategies will be applied, combining genetic techniques (genotyping) and several parametric and nonparametric statistical methode.

                                                                        Researcher(s)

                                                                        Research team(s)

                                                                          VIB-Genetic and physical analysis of Alzheimer disease genes. 01/04/1998 - 31/03/2000

                                                                          Abstract

                                                                          In 40 to 60% of the Alzheimer disease (AD) patients, the disease has a genetic aetiology, in most cases involving multiple genes and environmental factors. Three genes (APP, PSEN1 and PSEN2) and 1 genetic risk Factor (APOE) are identified, and other risk factors are suggested. This project aims at further genetic analyses of AD and the study of genotype-phenotype correlations. Additional AD genes will be identified by genetic linkage analyses, risk genes by genetic association studies. The genotype-phenotype correlation studies with mainly focus on unusual mutations that we previously identified.

                                                                          Researcher(s)

                                                                          Research team(s)

                                                                            VIB-Cloning and identification of a gene on chromosome 18q22 or elsewhere in the genome. 01/01/1998 - 31/12/2001

                                                                            Abstract

                                                                            The goal of this project is to clone and characterize a gene for mood disorders. From the candidate region on chromosome 18q22 a YAC contig was constructed. This YAC contig will be used to isolate region specific triplet repeats and new candidate genes using the exontrapping technique. New triplet repeats are analyzed for expansions and known and new candidate genes are analyzed for mutations using direct cDNA sequencing. Once the gene has been cloned we will unravel the genomic structure of this gene. This implicates the determination of the intron-exon boundaries and the analysis and characterization of the promoter region.

                                                                            Researcher(s)

                                                                            Research team(s)

                                                                              Molecular genetic analysis of normal phenotypic characteristics in relation to complex multifactorial diseases of the central nervous system. 01/01/1998 - 31/12/2001

                                                                              Abstract

                                                                              The aim of this study is to identify genetic variations that are associated with the normal phenotypic traits memory and personality. The rationale behind this study is that these genetic variations, either alone or in combinations, are genetic susceptibility loci for complex multifactorial diseases, in this case Alzheimer disease and manic depressive illness. The proposed project is a new and alternative approach towards identifying genetic susceptibility loci for complex multifactorial diseases starting from genetic variations in normal phenotypic traits.

                                                                              Researcher(s)

                                                                              Research team(s)

                                                                                Molecular genetic analysis of complex psychiatric diseases including personality. 01/01/1998 - 31/12/2001

                                                                                Abstract

                                                                                Our laboratory has a 10 year tradition in the research of bipolar disorder (BP). The genetic analysis of BP is extremely coinplex. In this project we propose to identify genes that influence personality in healthy populations. Using the "Tridimensional Personality Questionnaire" and the "Temperament and Character lnventory", 4 independently inherited temperamentdimensions (Novelty Seeking, liarm Avoidance, Persistence, Reward Dependence) can be quantified. Using a case-control strategy, associations between candidate genes and these teinperamentdimensions will be identified and correlated with complex disorders such as BP.

                                                                                Researcher(s)

                                                                                Research team(s)

                                                                                  Molecular genetic and functional analysis of genes involved in inherited peripheral neuropathies and hereditary ataxia's. 01/01/1998 - 31/12/2000

                                                                                  Abstract

                                                                                  The goal of this project is to clone and characterize the gene for ADCAII (SCA7). Hereto, The YACs from the minimal tiling path will be subcloned in the multiple exon trap cosmid vector, sCOGH6. Obtained cosmid clones will be screened for the presence of human/CAG sequences and subsequently these sequences will be analyzed for CAG expansions reading to the disease. Once the gene has been cloned we will unravel the genomic structure of this gene. This implicates the determination of the intron-exon boundaries and the analysis and characterization of the promoter region.

                                                                                  Researcher(s)

                                                                                  Research team(s)

                                                                                    VIB-Positional cloning of Charcot-Marie-Tooth type 2 (CMT2). 01/01/1998 - 31/12/1998

                                                                                    Abstract

                                                                                    Charcot-Marie-Tooth disease (CMT) is the most frequent inherited disorder of the peripheral nervous system. CMT type 2 is the neuronal form of CMT without alterations of the myelin sheath. No genes have been identified for CMT2. This research grant aims to 1) confirm the known CMT2 loci that have been mapped on chromosomes l, 3, 7 and X, 2) perform a genome -wide search for the CMT2 loci in unlinked CMT2 families, 3) construct physical maps of the linked regions in order to isolate gene(s), 4) mutation analysis of positional and functional candidate genes in order to identify the disease causing mutation(s).

                                                                                    Researcher(s)

                                                                                    Research team(s)

                                                                                      VIB-European collaborative study on molecular genetics in affective disorders. 01/12/1997 - 30/11/2000

                                                                                      Abstract

                                                                                      The main objective of this project is to test in a powerful European sample of bipolar and unipolar depression patients whether proposed candidate genes and chromosomal regions play a role in the aetiology of these disorders. Eight European centers will collaborate in this large scale multidisciplinary effort to generate a database of more than 1300 individuals with genotype information. The quantitative effects of some relevant psychosocial vulnerability factors on gene expression will be evaluated through association, sib-pair and linkage analyses.

                                                                                      Researcher(s)

                                                                                      Research team(s)

                                                                                        Molecular genetic analysis of Alzheimer dementie. 01/10/1997 - 30/09/2000

                                                                                        Abstract

                                                                                        Currently, 3 genes are identified that, when mutated, cause presenile Alzheimer dementie (AD). Senile AD is at least partly caused by genetic factors. However, the currently known causal AD genes and genetic risk factors cannot explain all AD cases. The aim of this project is to identify new causative genes in autosomal dominant AD families, and genetic risk and protection factors in complex familial and non-familial forms of AD.

                                                                                        Researcher(s)

                                                                                        Research team(s)

                                                                                          Localisation and identification of the gene responsible for distal hereditary motor neuropathy type. 01/10/1997 - 01/09/2000

                                                                                          Abstract

                                                                                          The distal hereditary motor neuropathy (distel HMN) or the spinel form of Charcot-MarieTooth disease is a motor disorder of the peripheral nervous system. A previous linkage study in a multi-generational Belgian family with autosomal dominant distel HMN type II showed significant linkage for markers located at 12q24. A 13 cM interval between D12S86 and D12S340 could be delineated as the candidate region for distal HMN II. We are currently constructing a physical map of the candidate region in order to clone the gene causing distal HMN type TT. A few genes with a function in the peripheral nervous system have been described within the 12q23.1 -24 region. Fine mapping of these genes will leed to the exact localization within the candidate region. A mutation analysis of the potential candidate genes will be performed in the patients using methode such as direct sequencing, Southern blotting, SSCP gel electrophoresis and RT- PCR mutation analysis. If no mutations can be found in the described candidate genes or ESTs, exon-trapping and direct cDNA selection can be applied for the localization and identification of unknown genes within the candidate region.

                                                                                          Researcher(s)

                                                                                          Research team(s)

                                                                                            In vitro functional analysis of gene defects and genetic risk factors responsible for presenile Alzheimer dementia. 01/10/1997 - 30/09/1999

                                                                                            Abstract

                                                                                            Gene defects (especially in presenilin genes), that are responsible for Alzheimer dementia, will be functionally analysed. Therefore cDNA transfections are performed in different cell lines also patient cells are held in culture. Presenilin metabolism in the presence of presenilin mutations will be studied as well as the influence of the presenilin genes on the APP metabolism.

                                                                                            Researcher(s)

                                                                                            Research team(s)

                                                                                              Cloning of genes containing expanded trinucleotide repeats in bipolar affective disorder. 01/10/1997 - 30/09/1999

                                                                                              Abstract

                                                                                              This project aims to clone genes with expanded triplet repeats. For this purpose one can start from total genomic DNA or from cloned sequences. Triplet repeats can be isolated from total genomic DNA by existing techniques (e.g. DIRECT) or by implementing new hybridisation-based techniques. Triplet repeats from cloned sequences will be isolated by screening cDNA libraries, regio specific genomic libraries and YACs with the corresponding triplet containing repeat oligonucleotides.

                                                                                              Researcher(s)

                                                                                              Research team(s)

                                                                                                VIB-Cloning of genes containing expanded trinucleotide repeats in bipolar affective disease. 01/08/1997 - 31/07/2000

                                                                                                Abstract

                                                                                                Several independent studies have shown the presence of clinical anticipation in bipolar affective disorder (BPAD). Anticipation, particularly in CNS disorders, are often caused by expanded trinucleotide DNA sequences in or near genes. The aim of this collaborative European study is to develop novel cloning techniques for trinucleotide repeat expansions, to identify trinucleotide repeat expansions involved in BPAD and to isolate their associated genes.

                                                                                                Researcher(s)

                                                                                                Research team(s)

                                                                                                  A genome-wide search for the gene(s) responsible for Charcot-Marie-Tooth type 2 (CMT2). 01/04/1997 - 31/03/1999

                                                                                                  Abstract

                                                                                                  This project is a renewal of a previous project with the aim to identify a gene or genes reponsible for Charcot-Marie-Tooth type 2 (CMT2) disease or the axonal form of CMT. A genome-wide search will be performed with highly polymorphic DNA markers. Once a localisation if found, molecular genetic studies will be performed to identify the gene and mutation responsible for this disease.

                                                                                                  Researcher(s)

                                                                                                  Research team(s)

                                                                                                    Genetic analysis of PS genes in early-onset Alzheimer disease. 01/04/1997 - 31/03/1998

                                                                                                    Abstract

                                                                                                    Mutations in presenilin-1 are a frequent genetic cause of familial Alzheimer disease (AD), while mutations in presenilin-2 are rare. We aim to determine realistic mutation frequencies by performing extensive mutation analyses of the presenilin genes in a unique set of presenile familial and non-familial AD patients, obtained in a population-based study of dementie in The Netherlands. Also, our mutation analyses can identify new polymorphisms that can be used in genetic association studies.

                                                                                                    Researcher(s)

                                                                                                    Research team(s)

                                                                                                      Alzheimer disease : functional analysis of the proteins. 01/01/1997 - 31/12/2001

                                                                                                      Abstract

                                                                                                      Alzheimer's disease (AD) is a fatal progressive form of dementia. In 10% of the cases AD is inherited as an autosomal dominant trait. Three AD-genes have been identified: the amyloid precursor protein (APP), the presenilin-1 (PS-1) and presenilin-2 (PS-2) gene. The aim of this research project is to investigate the metabolism of the proteins encoded by these genes and to study the relationship between the AD-associated proteins (APP, AB amyloid, tau, PS-1/2). Furthermore the subcellular localisation and the distribution pattern of these proteins in human brain tissue of AD-patients and controls, will be studied. Since this research demands a multidisciplinary approach (biotechnology, cell culture work, light -immunofluorescence - and electron microscopy), a close collaboration between the laboratories of Neurogenetics and Neuropathology) is established.

                                                                                                      Researcher(s)

                                                                                                      Research team(s)

                                                                                                        Molecular genetical and functional analysis of genes involved in hereditary motor and/or sensory neuropathies. 01/01/1997 - 31/12/2000

                                                                                                        Abstract

                                                                                                        In this project we will use a genome-wide search for genes involved in the different forms of Charcot-Marie-Tooth neuropathy. Also, we will use cellular and animal models to examine the role of disease genes in the neuropathy. Special attention will be given to the myeline Po gene.

                                                                                                        Researcher(s)

                                                                                                        Research team(s)

                                                                                                          Isolation and characterization of the chromosome 14 linked gene encoding presenile Alzheimer dementia. 01/01/1997 - 31/12/1998

                                                                                                          Abstract

                                                                                                          The aim of this project is the genomic characterization of the chromosome 14q24.3 linked presenile Alzheimer dementia gene, PSEN1. In addition to the delineation of the complete genomic structure we will optimize techniques to isolate and characterize the promoter and other regulatory sequences of PSEN1.

                                                                                                          Researcher(s)

                                                                                                          Research team(s)

                                                                                                            Identification of candidate genes for chromosome 14 encoded presenile Alzheimer dementia using direct cDNA selection. 01/01/1997 - 31/12/1998

                                                                                                            Abstract

                                                                                                            This project aims at isolating candidate genes coding for presenile Alzheimer dementia in the minimale candidate region on chromosome 14. First, the YAC-cantig has to be converted in a "minimal tiling path". Genes shall be selected from this "minimal tiling path" through the direct selection technique. Candidate cDNA's genes will undergo a mutation analysis in order to find the AD3-gene.

                                                                                                            Researcher(s)

                                                                                                            Research team(s)

                                                                                                              Positional cloning of distal hereditary motor neuropathy type II (distal HMN II). 01/01/1997 - 31/12/1997

                                                                                                              Abstract

                                                                                                              The distal hereditary motor neuropathy type II (distal HMN II) or the spinal form of Charcot-Marie-Tooth (CMT) is a rare disorder of the peripheral nervous system. In 1996, we found genetic linkage to chromosome 12q24 in a Belgian distal HMN II family. This project aims to identify the gene defect responsible for the distal HMN II phenotype. To assemble a clone contig of the distal HMN II region, we use yeast artificial chromosomes (YACs), P1-phage derived artificial chromosomes (PACs), cosmids, radiation hybrids (RH) and pulsed field gel electrophoresis (PFGE). Also, positional and functional candidate genes will be analysed for the presence of mutations.

                                                                                                              Researcher(s)

                                                                                                              Research team(s)

                                                                                                                Molecular genetic research of Charcot-Marie-Tooth neuropathy and related disorders. 05/12/1996 - 05/12/1999

                                                                                                                Abstract

                                                                                                                This project aims at localizing the gene of genes for Charcot-Marie-Tooth disease type 2, a peripheral neuropathy. Once the chromosomal location is known, we will use molecular genetic techniques to identify the gene and gene mutation.

                                                                                                                Researcher(s)

                                                                                                                Research team(s)

                                                                                                                  VIB-Transgeneric mouse and rat models for AlzheimerÆs disease. 01/11/1996 - 30/10/1999

                                                                                                                  Abstract

                                                                                                                  The aim of this project is to create a transgenic mouse model for Alzheimer's disease (AD), a progressive form of dementia. Most AD cases occur sporadically but in 10 % of the cases AD is inherited as an autosomal dominant trait. Three AD genes have been identified: the amyloid precursor protein (APP), the presenilin-l (PS-1) and presenilin-2 (PS-2) gene. In first place we focused on a transgenic mouse model for the formation of the A6 amyloid deposition in the brain in AD patients by creating a mouse overexpressing a mutant APP gene. This model will allow testing of the hypothesis that development of the amyloid plaques in specific brain regions is a primary cause of neurodegeneration and failing behaviour. Secondly, overexpressing mutant PS- 1 mouse model will be created.

                                                                                                                  Researcher(s)

                                                                                                                  Research team(s)

                                                                                                                    Clinical, genetical and functional analysis of peripheral neuropathies : an integratery approach. 01/11/1996 - 31/03/1999

                                                                                                                    Abstract

                                                                                                                    This project is a concerted action comprising around 60 European laboratories active in the field of the genetical, clinical and functional studies of peripheral neuropathies of the type Charcot-Marie-Tooth. An important goal is to enhance transmission of information through scientific meetings and workshops.

                                                                                                                    Researcher(s)

                                                                                                                    Research team(s)

                                                                                                                      VIB-Probing the cellular function of the early-onset AlzheimerÆs disease preseneline-1 protein. 01/10/1996 - 30/09/1999

                                                                                                                      Abstract

                                                                                                                      AlzheimerÆs disease (AD) is a fatal, neurodegenerative disorder, characterised by a progressive dementia. In addition to the presence of extracellular senile plaques, AD is pathologically identified by the presence of intracellular neurofibrillary tangles in the brain. These neurofibrillary tangles are primarily composed of the microtubuli associated protein, tau, which appears in a hyperphosphorylated state. Three genes have been identified to cause AD: The amyloid precursor protein (APP), the presenilin-l (PS-1) and presenilin-2 (PS-2). The aim of this research project is to investigate how PS proteins are involved in AD-pathogenesis. The following questions regarding PS-1 mutants will be addressed: I)The putative influence on APP and Abamyloid processing in neuronal cells, 2) The relation with Ab-amyloid induced neurotoxicity, in particular the interference with the Ca2+ homeostasis. 3) The effect on modifications of the cytoskeleton, in particular tau phosphorylation.

                                                                                                                      Researcher(s)

                                                                                                                      Research team(s)

                                                                                                                        Molecular genetic analysis of the brachial plexus neuropathy (Hereditary Neuralgic Amyotrophy, HNA). 01/10/1996 - 30/09/1998

                                                                                                                        Abstract

                                                                                                                        HNA is a rare autosomal dominant neuropathy characterised by episodes of attacks of pain followed by muscle weakness and sensory disturbances due to brachial plexus neuritis. Recently, a genetic linkage study in two American HNA families suggested a HNA locus on chromosome 17q. Segregation analysis of STR markers in a Turkish pedigree refined the HNA locus to a 16 cM region on chromosome 17q24-25. In this research, we aim to identify the HNA gene / mutation. After refinement of the HNA locus we will construct a physical map of the minimal linkage region using yeast artificial chromosomes (YACs). The YAC-contig will be subcloned in sCOGH cosmids. After exontrapping or direct cDNA selection on this cosmid library, mutation analysis on the subtracted genes may lead to the identification of the HNA gene. This will lead to a better understanding of the HNA aetiology and related peripheral neuropathies and provide a DNA diagnosis for HNA patients and asymptomatic individuals.

                                                                                                                        Researcher(s)

                                                                                                                        Research team(s)

                                                                                                                          In vitro study on the possible influence of presenilin mutations on tau phosphylation and cell death. 01/10/1996 - 30/09/1998

                                                                                                                          Abstract

                                                                                                                          Alzheimer's disease (AD) is a fatal, neurodegenerative disorder, characterised by a progressive dementia. In addition to the presence of extracellular senile plaques, AD is pathologically identified by the presence of intracellular neurofibrillary tangles in the brain. These neurofibrillary tangles are primarily composed of the microtubuli associated protein, tau, which appears in a hyperphosphorylated state. Recently, the presenilin-l (PS-1) and presenilin-2 (PS-2) gene were identified. When mutated these genes cause AD. The aim of this IWETO research project is to develop an in vitro model to study how PS-1/2 mutations can lead to AD pathogenesis. In this frame the possible influence of PS-1/2 mutations on tau phosphorylation will be studied. Intracellular Ca2+ concentrations will be measured in PS-1/2 cDNA transfected cells. Finally, we will examine whether apoptosis (programmed cell death occurs in PS-1/2 overexpressing cells.

                                                                                                                          Researcher(s)

                                                                                                                          Research team(s)

                                                                                                                            Genetic and functional analysis of wild type and mutated presenilin-1 gene in relation to Alzheimer's disease. 01/10/1996 - 30/09/1997

                                                                                                                            Abstract

                                                                                                                            To study the normal and pathological functions of the presenilin-1 protein, the genomic structure of the complete gene will be determined. Genomic clones containing the presenilin-1 gene (wild type or mutated) will be used in cellular models and animal models to study the gene/protein function in relation to Alzheimer's disease.

                                                                                                                            Researcher(s)

                                                                                                                            Research team(s)

                                                                                                                              Positional cloning of the neuronal and spinal forms of Charcot-Marie-Tooth neuropathy. 01/07/1996 - 31/12/2001

                                                                                                                              Abstract

                                                                                                                              The project aims at cloning the disease genes for the spinal and neuronal forms of Charcot-Marie-Tooth neuropathy, using a positional cloning approach. First, the gene is localised to a specific chromosonal area by segregation studies in disease families. Second, the gene is cloned using recombinant DNA technology.

                                                                                                                              Researcher(s)

                                                                                                                              Research team(s)

                                                                                                                                Transcriptional mapping of chromosome 21. 01/07/1996 - 31/12/1998

                                                                                                                                Abstract

                                                                                                                                This project aims at construction a complete transcriptional map of human chromosome 21 using the following strategy : construction of a complete physical map; construction of a ready to sequence contig map; identification of genes by exon trapping and direct cDNA selection; characterization of the expression pattern of genes. Our group is responsible for chromosome 21.

                                                                                                                                Researcher(s)

                                                                                                                                Research team(s)

                                                                                                                                  Transcriptional mapping of chromosome 21; physical mapping prior to sequencing; sequencing of the Down syndrome chromosome region. 01/06/1996 - 31/05/1998

                                                                                                                                  Abstract

                                                                                                                                  This project aims at constructing a complete transcriptional map of human chromosome 21. Strategy used : construction of a complete physical map; construction of a ready to sequence map; identification of genes by exon strapping and direct cDNA selection; characterization of the expression pattern of genes.

                                                                                                                                  Researcher(s)

                                                                                                                                  Research team(s)

                                                                                                                                    Localisation and identification of genes involved in Charcot-Marie-Tooth neuropathy and related diseases. 01/06/1996 - 30/11/1996

                                                                                                                                    Abstract

                                                                                                                                    This project aims at studying the effect of different mutations on the normal functioning of myeline Po in relation to Charcot-Marie-Tooth neuropathy. Mutated Po cDNAs will be transfected in Schneider 2 cells to study adhesion. Mutated Po genes will be transfected in mouse embryonic cells to create transgenic mice.

                                                                                                                                    Researcher(s)

                                                                                                                                    Research team(s)

                                                                                                                                      Clinical, genetical and functional analysis of peripheral neuropathies : an integratery approach. 01/04/1996 - 30/09/1999

                                                                                                                                      Abstract

                                                                                                                                      This project is a concerted action comprising around 60 European laboratories active in the field of the genetical, clinical and functional studies of peripheral neuropathies of the type Charcot-Marie-Tooth. An important goal is to enhance transmission of information through scientific meetings and workshops.

                                                                                                                                      Researcher(s)

                                                                                                                                      Research team(s)

                                                                                                                                        Institutional funds VIB8: Department of Molecular Genetics. 01/01/1996 - 31/12/2001

                                                                                                                                        Abstract

                                                                                                                                        Genes and genetic risk factors are being searched for different complex neurological and neuropsychiatric diseases. Knowledge of these genes will help us to understand the underlying pathology of these diseases and ultimately lead to a more effective therapy.

                                                                                                                                        Researcher(s)

                                                                                                                                        Research team(s)

                                                                                                                                          Localisation and cloning of genes predisposing to complex neuropsychatric diseases. 01/01/1996 - 31/12/1999

                                                                                                                                          Abstract

                                                                                                                                          Alternative methods such as repeat expansion detection RED, genomic mismatch scanning GMS and representational difference analysis RDA will be examined to see whether they allow the identification of genes predisposing to complex neurological and neuropsychiatric diseases.

                                                                                                                                          Researcher(s)

                                                                                                                                          Research team(s)

                                                                                                                                            Molecular genetic analysis of Alzheimer dementia. 01/01/1996 - 31/12/1998

                                                                                                                                            Abstract

                                                                                                                                            The project aims to evaluate the contribution of the different known genes for presenile Alzheimer dementia (AD): APP, PS-l en PS-2. We have access to an epidemiological ascertained sample of 100 presenile AD patients. Mutations will be detected by SSCP ananlysis and direct PCR sequencing.

                                                                                                                                            Researcher(s)

                                                                                                                                            Research team(s)

                                                                                                                                              Eficiency of gene therapy in human hematopoietic cells. 01/01/1996 - 31/12/1997

                                                                                                                                              Abstract

                                                                                                                                              We will study the efficiency of transduction in various hematopoietic cells, as well as the efficiency of expression after transduction, depending on different promotors. The use of different promotors will enable to observe wheter there is a preferential expression of the transduced gene in the various cells that one wishes to influence by gene-therapy; hematopoietic cells.

                                                                                                                                              Researcher(s)

                                                                                                                                              Research team(s)

                                                                                                                                                Localisation and cloning of genes predisposing to complex neuropsychatric diseases. 01/01/1996 - 31/12/1996

                                                                                                                                                Abstract

                                                                                                                                                Alternative methods such as repeat expansion detection RED, genomic mismatch scanning GMS and representational difference analysis RDA will be examined to see whether they allow the identification of genes predisposing to complex neurological and neuropsychiatric diseases.

                                                                                                                                                Researcher(s)

                                                                                                                                                Research team(s)

                                                                                                                                                  Functional analysis of mutations in the myelin gene Po associated with Charcot-Marie-Tooth disease, type I. 01/01/1996 - 31/12/1996

                                                                                                                                                  Abstract

                                                                                                                                                  Different mutations were detected in the myeline gene Po responsible for Charcot-Marie-Tooth neuropathy, type I. This project aims to study the effect of these mutations on normal functioning of the Po protein and this in relation to the disease pathology.

                                                                                                                                                  Researcher(s)

                                                                                                                                                  Research team(s)

                                                                                                                                                    Functional analysis of mutations in the peripheral myelin protein zero gene (PO) associated with Charcot-Marie-Tooth disease type 1. 01/10/1995 - 30/09/1998

                                                                                                                                                    Abstract

                                                                                                                                                    Charcot-Marie-Tooth disease type 1, a disorder of the peripheral nervous system, is genetically heterogeneous with loci on chromosomes 1, 17 and X. We identified different mutations in the PO gene on chromosome 1. The aim of this project is a functional analysis of P0 mutations. A first approach is in vitro analysis, in a later stage in vivo experiments will be performed. Knowledge about the pathogenesis of CMT1 can give us insights about the functioning of the peripheral nervous system. Insights in the pathogenesis of the disease are a first step towards the development of an effective therapy. Transgenic animals can act as a model for human neuropathies to test therapies.

                                                                                                                                                    Researcher(s)

                                                                                                                                                    Research team(s)

                                                                                                                                                      In vitro functional analysis of gene defects and genetic risk factors responsible for presenile Alzheimer dementia. 01/10/1995 - 30/09/1997

                                                                                                                                                      Abstract

                                                                                                                                                      Gene defects (especially in presenilin genes), that are responsible for Alzheimer dementia, will be functionally analysed. Therefore cDNA transfections are performed in different cell lines also patient cells are held in culture. Presenilin metabolism in the presence of presenilin mutations will be studied as well as the influence of the presenilin genes on the APP metabolism.

                                                                                                                                                      Researcher(s)

                                                                                                                                                      Research team(s)

                                                                                                                                                        Allelic association studies in chromosome 14 linked Alzheimer' disease. 01/04/1995 - 31/03/1997

                                                                                                                                                        Abstract

                                                                                                                                                        This project examines if allelic association exists in patients with Alzheimer disease encoded by chromosome 14. Allelic association allows to narrow down the chromosome region that encompasses the gene defective in these families. To examine allelic association we will use material of two large families known as AD/A and AD/B.

                                                                                                                                                        Researcher(s)

                                                                                                                                                        Research team(s)

                                                                                                                                                          A genome-wide search for the gene(s) responsible for Charcot-Marie-Tooth neuropathy type 2. 01/04/1995 - 31/03/1997

                                                                                                                                                          Abstract

                                                                                                                                                          This project aims at the identification of a gene (or genes) for Charcot-Marie-Tooth neuropathie type 2, a peripethal nervous system degenerative disease. A genome-wide search will be performed using highly polymorphic DNA markers. Once a localisation is found molecular genetic techniques will be applied to identify the gene and mutation responsible for this disease.

                                                                                                                                                          Researcher(s)

                                                                                                                                                          Research team(s)

                                                                                                                                                            Cloning of the chromosome 14q24.3 gene for familial presenile Alzheimer dementia. 01/01/1995 - 31/12/1998

                                                                                                                                                            Abstract

                                                                                                                                                            This project aims at isolating the gene and identifying the mutation responsible for chromosome 14 encoded presenile Alzheimer dementia. First the candidate region at 14q24.3 will be cloned in YACs and cosmids. Next candidate genes will be isolated using direct cDNA selection and exon amplification techniques. These genes will be analysed for mutations in order to identify the disease gene.

                                                                                                                                                            Researcher(s)

                                                                                                                                                            Research team(s)

                                                                                                                                                              Identification of candidate genes for chromosome 14 encoded presenile Alzheimer dementia using exon amplification. 01/01/1995 - 31/12/1996

                                                                                                                                                              Abstract

                                                                                                                                                              This project aims at isolating the candidate genes for chromosome 14 encoded presenile Alzheimer dementia using the exon amplification technique. These genes will be screened for mutations in order to identify the disease gene.

                                                                                                                                                              Researcher(s)

                                                                                                                                                              Research team(s)

                                                                                                                                                                Identification of candidate genes for chromosome 14 encoded presenile Alzheimer dementia using direct cDNA selection. 01/01/1995 - 31/12/1996

                                                                                                                                                                Abstract

                                                                                                                                                                This project aims at isolating candidate genes coding for presenile Alzheimer dementia in the minimale candidate region on chromosome 14. First, the YAC-cantig has to be converted in a "minimal tiling path". Genes shall be selected from this "minimal tiling path" through the direct selection technique. Candidate cDNA's genes will undergo a mutation analysis in order to find the AD3-gene.

                                                                                                                                                                Researcher(s)

                                                                                                                                                                Research team(s)

                                                                                                                                                                  Prefinancing: Institutional funds VIB8: Department of Molecular Genetics. 01/01/1995 - 31/12/1995

                                                                                                                                                                  Abstract

                                                                                                                                                                  Genes and genetic risk factors are being searched for different complex neurological and neuropsychiatric diseases. Knowledge of these genes will help us to understand the underlying pathology of these diseases and ultimately lead to a more effective therapy.

                                                                                                                                                                  Researcher(s)

                                                                                                                                                                  Research team(s)

                                                                                                                                                                    Molecular genetic analysis of hereditary ataxias. 01/10/1994 - 30/09/1996

                                                                                                                                                                    Abstract

                                                                                                                                                                    The method of positional cloning will be used to identify the chromosomal loci for hereditary ataxias such as Spinocerebellar ataxia and spastic paraplegia. Subsequently the respective genes will be cloned and the mutations identified.

                                                                                                                                                                    Researcher(s)

                                                                                                                                                                    Research team(s)

                                                                                                                                                                      New genetic approaches towards cloning of genes predisposing to complex neuropsychiatric diseases. 01/10/1994 - 31/12/1995

                                                                                                                                                                      Abstract

                                                                                                                                                                      The aim of this study is to identify genes that are responsible for complex neuropsychiatric diseases such as manic depressive illness on schizophrenia. Knowledge of the function of these genes would help not only to diagnose the disease more accurately, but also to develop a more direct therapy.

                                                                                                                                                                      Researcher(s)

                                                                                                                                                                      Research team(s)

                                                                                                                                                                        Transgenic mouse model for Alzheimer disease. 01/06/1994 - 30/05/1996

                                                                                                                                                                        Abstract

                                                                                                                                                                        The aim is to develop by transgenic technology, a mouse model for the formation of the B-amyloid deposits in the brain in Alzheimer disease patients. It will test the hypothesis that development of the amyloid plaques in specific brain areas is a prime cause of neurodegeneration and failing behaviour.

                                                                                                                                                                        Researcher(s)

                                                                                                                                                                        Research team(s)

                                                                                                                                                                          Construction of an integrated overlap, physical, genetic and transcriptional map of the chromosome 21. 01/01/1994 - 31/12/1995

                                                                                                                                                                          Abstract

                                                                                                                                                                          This project is a collaborative study of different European labs that are involved in the construction of a complete map of human chromosome 21 using physical and genetical mapping techniques such as linkage analysis, pulsed field gel electrophoresis, somatic cell hybrids, YAC cloning, FISH etc. This map must allow for the identification of chromosome 21 specific genes.

                                                                                                                                                                          Researcher(s)

                                                                                                                                                                          Research team(s)

                                                                                                                                                                            Study of the genetical factors in the etiology of schizophrenia and manic depressive psychosis 01/01/1994 - 31/12/1994

                                                                                                                                                                            Abstract

                                                                                                                                                                            This project includes the study of genetically loaded families with schizophrenia or manic depressive psychosis in order to localize, to isolate and to indentify genes involved in the disease process.

                                                                                                                                                                            Researcher(s)

                                                                                                                                                                            Research team(s)

                                                                                                                                                                              Adaptive value of partner choice and cuckoldry. 01/01/1994 - 31/12/1994

                                                                                                                                                                              Abstract

                                                                                                                                                                              In this study we investigate in several bird species which criteria are used in partnerchoice, with whom, when and how frequently females copulate (sperm competition), and to what extent variation in this behaviour is adaptive.

                                                                                                                                                                              Researcher(s)

                                                                                                                                                                              Research team(s)

                                                                                                                                                                                A genome-wide search for the distal hereditary motor neuropathy gene. 01/01/1994 - 31/12/1994

                                                                                                                                                                                Abstract

                                                                                                                                                                                In order to localize the gene for distal hereditary motor neuropathy type II (distal HMN II), we plan a random search of the whole human genome using preferably highly informative DNA markers. We would like to perform this genome-wide search with the facilities of the Human Genome Research Centre, Généthon in Paris.

                                                                                                                                                                                Researcher(s)

                                                                                                                                                                                Research team(s)

                                                                                                                                                                                  Positional cloning of Charcot-Marie-Tooth neuropathy, type 2. 01/10/1993 - 05/12/1996

                                                                                                                                                                                  Abstract

                                                                                                                                                                                  This project aims at localizing the gene of genes for Charcot-Marie-Tooth disease type 2, a peripheral neuropathy. Once the chromosomal location is known, we will use molecular genetic techniques to identify the gene and gene mutation.

                                                                                                                                                                                  Researcher(s)

                                                                                                                                                                                  Research team(s)

                                                                                                                                                                                    Genetic linkage studies in manic depressive psychosis. 01/10/1993 - 30/09/1995

                                                                                                                                                                                    Abstract

                                                                                                                                                                                    Family-, adoption- and twinstudies suggested the involvement of genetic factors in the aetiology of manic depression, a severe cyclic mental illness. Using restriction fragment length polymorphisms and linkage studies we try to find the predisposing gene.

                                                                                                                                                                                    Researcher(s)

                                                                                                                                                                                    Research team(s)

                                                                                                                                                                                      Molecular genetic analysis of hereditary ataxias. 01/10/1993 - 30/09/1994

                                                                                                                                                                                      Abstract

                                                                                                                                                                                      The method of positional cloning will be used to identify the chromosomal loci for hereditary ataxias such as Spinocerebellar ataxia and spastic paraplegia. Subsequently the respective genes will be cloned and the mutations identified.

                                                                                                                                                                                      Researcher(s)

                                                                                                                                                                                      Research team(s)

                                                                                                                                                                                        Localisation, cloning and expression of genes responsible for neurological disorders. 01/01/1993 - 31/12/1996

                                                                                                                                                                                        Abstract

                                                                                                                                                                                        Using the method of positional cloning we will search for genes responsible for inherited neurological disorders such as Alzheimer's disease and Charcot-Marie-Tooth neuropathy. Subsequently we will study the function(s) of the disease gene in vitro in cell cultures and in vivo in transgenic mice.

                                                                                                                                                                                        Researcher(s)

                                                                                                                                                                                        Research team(s)

                                                                                                                                                                                          Localisation and identification of genes responsible for Charcot-Marie-Tooth neuropathy and related disorders. 01/01/1993 - 31/12/1996

                                                                                                                                                                                          Abstract

                                                                                                                                                                                          Charcot-Marie-Tooth neuropathy is a genetically hetero-geneous disorder. Only a few genes have been identified. We will use the method of positional cloning to localise new genes and to identify the responsible mutations. These mutations may help to sustain clinical diagnosis and to understand the pathogenesis of the disease.

                                                                                                                                                                                          Researcher(s)

                                                                                                                                                                                          • Promotor: Van Broeckhoven Christine
                                                                                                                                                                                          • Co-promotor: De Jonghe Peter
                                                                                                                                                                                          • Co-promotor: Martin Jean-Jacques
                                                                                                                                                                                          • Co-promotor: Raeymaekers Peter

                                                                                                                                                                                          Research team(s)

                                                                                                                                                                                            Adaptive value of partner choice and cuckoldry. 01/01/1993 - 31/12/1996

                                                                                                                                                                                            Abstract

                                                                                                                                                                                            In this study we investigate in several bird species which criteria are used in partnerchoice, with whom, when and how frequently females copulate (sperm competition), and to what extent variation in this behaviour is adaptive.

                                                                                                                                                                                            Researcher(s)

                                                                                                                                                                                            Research team(s)

                                                                                                                                                                                              Analysis of the relation between the molecular genetic defect and the clinical phenotype in patients with Duchenne or Becker muscular dystrophy. 01/01/1993 - 31/12/1994

                                                                                                                                                                                              Abstract

                                                                                                                                                                                              Using modern techniques of molecular genetics such as multiple PCR analysis and pulsed field gel electrophoresis as well as immuno-histochemical analysis of muscle biopsy material with dystrophine antibodies we are trying to find a correlation between the clinical phenotype of Duchenne or Becker patients and their genetic defect.

                                                                                                                                                                                              Researcher(s)

                                                                                                                                                                                              Research team(s)

                                                                                                                                                                                                Localisation, cloning and expression of genes responsible for neurological disorders. 01/10/1992 - 31/12/1996

                                                                                                                                                                                                Abstract

                                                                                                                                                                                                Using the method of positional cloning we will search for genes responsible for inherited neurological disorders such as Alzheimer's disease and Charcot-Marie-Tooth neuropathy. Subsequently we will study the function(s) of the disease gene in vitro in cell cultures and in vivo in transgenic mice.

                                                                                                                                                                                                Researcher(s)

                                                                                                                                                                                                Research team(s)

                                                                                                                                                                                                  Molecular genetic analysis of hereditary ataxias. 01/10/1992 - 30/09/1993

                                                                                                                                                                                                  Abstract

                                                                                                                                                                                                  The method of positional cloning will be used to identify the chromosomal loci for hereditary ataxias such as Spinocerebellar ataxia and spastic paraplegia. Subsequently the respective genes will be cloned and the mutations identified.

                                                                                                                                                                                                  Researcher(s)

                                                                                                                                                                                                  Research team(s)

                                                                                                                                                                                                    Molecular genetic analysis of affective disorders. 01/10/1992 - 30/09/1993

                                                                                                                                                                                                    Abstract

                                                                                                                                                                                                    In a large sample of unrelated patients with affective disorders -bipolar or unipolar disease - we will use association studies (linkage disequilibrium study) of polymorphic markers to identify candidate genes involved in the pathogenesis of these disorders.

                                                                                                                                                                                                    Researcher(s)

                                                                                                                                                                                                    Research team(s)

                                                                                                                                                                                                      Genetic heterogeneity studies in families with hereditary motor and/or sensory neuropathies. 01/10/1992 - 30/09/1993

                                                                                                                                                                                                      Abstract

                                                                                                                                                                                                      A classification of all types and subtypes of hereditary motor and/or sensory neurpathies will be made using linkage analysis. This genetic classification will be correlated with the clinical classification.

                                                                                                                                                                                                      Researcher(s)

                                                                                                                                                                                                      Research team(s)

                                                                                                                                                                                                        Identification and expression of human genes related to Alzheimer's disease. 01/07/1992 - 30/06/1993

                                                                                                                                                                                                        Abstract

                                                                                                                                                                                                        Segregation analysis with polymorphic DNA markers in families with Alzheimer's disease enables the localization and isolation of defective genes. How these genes cause the disease as well as their normal function can than be studied in 'in vivo' and 'in vitro' expression systems.

                                                                                                                                                                                                        Researcher(s)

                                                                                                                                                                                                        Research team(s)

                                                                                                                                                                                                          Localisation, cloning and expression of genes responsible for neurological disorders. 01/01/1992 - 31/12/1994

                                                                                                                                                                                                          Abstract

                                                                                                                                                                                                          Using the method of positional cloning we will search for genes responsible for inherited neurological disorders such as Alzheimer's disease and Charcot-Marie-Tooth neuropathy. Subsequently we will study the function(s) of the disease gene in vitro in cell cultures and in vivo in transgenic mice.

                                                                                                                                                                                                          Researcher(s)

                                                                                                                                                                                                          Research team(s)

                                                                                                                                                                                                            Construction of an integrated overlap, physical, genetic and transcriptional map of the chromosome 21. 01/01/1992 - 30/06/1994

                                                                                                                                                                                                            Abstract

                                                                                                                                                                                                            This project is a collaborative study of different European labs that are involved in the construction of a complete map of human chromosome 21 using physical and genetical mapping techniques such as linkage analysis, pulsed field gel electrophoresis, somatic cell hybrids, YAC cloning, FISH etc. This map must allow for the identification of chromosome 21 specific genes.

                                                                                                                                                                                                            Researcher(s)

                                                                                                                                                                                                            Research team(s)

                                                                                                                                                                                                              Genetic linkage studies in manic depressive psychosis. 01/10/1991 - 30/09/1993

                                                                                                                                                                                                              Abstract

                                                                                                                                                                                                              Family-, adoption- and twinstudies suggested the involvement of genetic factors in the aetiology of manic depression, a severe cyclic mental illness. Using restriction fragment length polymorphisms and linkage studies we try to find the predisposing gene.

                                                                                                                                                                                                              Researcher(s)

                                                                                                                                                                                                              Research team(s)

                                                                                                                                                                                                                Linkage analysis of the Charcot-Marie-Tooth disease with genetic DNA markers. 01/10/1991 - 28/02/1993

                                                                                                                                                                                                                Abstract

                                                                                                                                                                                                                The Charcot-Marie-Tooth type 1a (CMT1a) disease or hereditary motor and sensory neuropathy type Ia is characterized by extensive de- and remyelination with highly reduced nerve conduction velocities. We try to localize the CMT1a gene on chromosome 17p11.2-p12 more precisely by using restriction fragment length polymorphisms, linkage analysis and pulsed field gelelectrophoresis.

                                                                                                                                                                                                                Researcher(s)

                                                                                                                                                                                                                Research team(s)

                                                                                                                                                                                                                  Genetic heterogeneity studies in families with hereditary motor and/or sensory neuropathies. 01/10/1991 - 30/09/1992

                                                                                                                                                                                                                  Abstract

                                                                                                                                                                                                                  A classification of all types and subtypes of hereditary motor and/or sensory neurpathies will be made using linkage analysis. This genetic classification will be correlated with the clinical classification.

                                                                                                                                                                                                                  Researcher(s)

                                                                                                                                                                                                                  Research team(s)

                                                                                                                                                                                                                    Localization and identification of the genes involved in Charcot-Marie-Tooth disease and related disorders. 01/01/1991 - 31/12/1991

                                                                                                                                                                                                                    Abstract

                                                                                                                                                                                                                    The Charcot-Marie-Tooth type 1a (CMT1a) disease is a clinically and genetically heterogeneous disorder of the peripheral nervous system. The aim of our project is to localize disease loci using segregation analysis in multiple affected families and to clone the respective genes by recombinant DNA technologies.

                                                                                                                                                                                                                    Researcher(s)

                                                                                                                                                                                                                    Research team(s)

                                                                                                                                                                                                                      Linkage analysis of the Charcot-Marie-Tooth disease with genetic DNA markers. 01/10/1990 - 30/09/1991

                                                                                                                                                                                                                      Abstract

                                                                                                                                                                                                                      The Charcot-Marie-Tooth type 1a (CMT1a) disease or hereditary motor abd sensory neuropathy type Ia is characterized by extensive de- and remyelination with highly reduced nerve conduction velocities. We try to localize the CMTIa gene on chromosome 17p11.2-p12 more precisely by using restriction fragment lenght polymorphisms, linkage analysis and pulsed field gelelectrophoresis.

                                                                                                                                                                                                                      Researcher(s)

                                                                                                                                                                                                                      Research team(s)

                                                                                                                                                                                                                        Genetic linkage studies in manic depressionì 01/10/1990 - 30/09/1991

                                                                                                                                                                                                                        Abstract

                                                                                                                                                                                                                        Family-, adoption- and twinstudies suggested the involvement of genetic factors in the aetiology of manic depression, a severe cyclic mental illness. Using restriction fragment length polymorphisms and linkage studies we try to find the predisposing gene.

                                                                                                                                                                                                                        Researcher(s)

                                                                                                                                                                                                                        Research team(s)

                                                                                                                                                                                                                          Genetic heterogeneity studies in families with hereditary motor and/or sensory neuropathies. 01/10/1990 - 30/09/1991

                                                                                                                                                                                                                          Abstract

                                                                                                                                                                                                                          Charcot-Marie-Tooth disease can be classified according to clinical, genetic and neurological characteristics. Currently, our laboratory has DNA of 29 CMT-families from different centres in West-Europe. First, we will perform a heterogeneity study of all CMT1 families by two- and multipoint analysis with markers of chromosomes 1, 17 and X. Second, we will analyse if CMT2 and other types of peripheral neuropathies also link to chromosome 1, 17 or X. If some families are not linked to the tested loci, we will analyse other chromosomes. A genetic heterogeneity study is currently the most useful method to unravel the complex nosology of the hereditary peripheral neuromuscular disorders. The knowledge of the genetic location of the different types of the disorder is not only a first step to the identification of the disease genes, but also a tool for clinical diagnostics.

                                                                                                                                                                                                                          Researcher(s)

                                                                                                                                                                                                                          Research team(s)

                                                                                                                                                                                                                            Identification of the genetic defect in neurological disorders using biotechnology methods. 01/01/1990 - 31/12/1992

                                                                                                                                                                                                                            Abstract

                                                                                                                                                                                                                            This project includes the study of the genetical aspects of Alzheimer's disease, Charcot-Marie-Tooth neuropathy and the affective disorders using the method of reverseal genetics.

                                                                                                                                                                                                                            Researcher(s)

                                                                                                                                                                                                                            Research team(s)

                                                                                                                                                                                                                              Recombinant DNA technology in neurological diseases. 01/10/1989 - 30/09/1995

                                                                                                                                                                                                                              Abstract

                                                                                                                                                                                                                              Positional cloning is a strategy that allows the localisation, isolation and identification of disease genes and subsequent analysis of their normal and pathogenic nature. Major projects are : Alzheimer's disease, Charcot-Marie-Tooth neuropathy, Duchenne muscular dystrophy, manic depressive illness.

                                                                                                                                                                                                                              Researcher(s)

                                                                                                                                                                                                                              Research team(s)

                                                                                                                                                                                                                                Linkage studies of chromosome 21 DNA markers with Alzheimer's disease. 01/10/1989 - 30/09/1991

                                                                                                                                                                                                                                Abstract

                                                                                                                                                                                                                                A chromosome 21 specific gene library was constructed and DNA markers were isolated and regionally mapped in different regions on chromosome 21. Markers from the proximal part of the long arm were used to identify DNA polymorphisms which can be useful in the genetic analysis in Alzheimer's disease and Down syndrome.

                                                                                                                                                                                                                                Researcher(s)

                                                                                                                                                                                                                                Research team(s)

                                                                                                                                                                                                                                  Identification and expression status of human genes involved in Alzheimer's disease. 01/01/1988 - 31/12/1992

                                                                                                                                                                                                                                  Abstract

                                                                                                                                                                                                                                  Applying reversed genetics techniques in large families with Alzheimer's disease to search and to characterize the molecular immutation underlying the disease.

                                                                                                                                                                                                                                  Researcher(s)

                                                                                                                                                                                                                                  Research team(s)