Bijdragen aan een beter inzicht in de genetische etiologie van de ziekte van Alzheimer

Datum: 20 oktober 2020

Locatie: ONLINE VERDEDIGING - - - - -

Tijdstip: 16 - 18 uur

Promovendus: Julie Hoogmartens

Promotor: Christine Van Broeckhoven, Rita Cacace

Korte beschrijving: Doctoraatsverdediging Julie Hoogmartens - Departement Biomedische Wetenschappen



Abstract

Alzheimer’s disease is a complex neurodegenerative disorder presenting at early (early-onset (EO) AD, ≤ 65 years) and late ages (late-onset (LO) AD, > 65 years) in familial and sporadic patients. Up to 60% of EOAD patients have a positive family history of dementia and 10-15% show clear autosomal dominant transmission. Linkage studies in large informative EOAD families with autosomal dominant inheritance have led to the identification of three causal genes - amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) - and a major risk factor - apolipoprotein E (APOE) e4 - and greatly improved our understanding of the pathomechanisms underlying AD. Causal mutations in APP, PSEN1 and PSEN2, however, explain only 5-10% of EOAD patients, leaving the majority of the patients genetically unexplained. Identification of novel genes will be key in further unravelling the complex molecular basis and pathological processes underlying AD etiology.

The general aim of this PhD project was to contribute to a better insight into the missing genetic etiology of AD using next generation sequencing (NGS). We used two different approaches, on the one hand, we performed a gene-discovery study using whole-genome sequencing (WGS) data of unrelated AD patients and on the other hand, we followed a hypothesis driven approach based on prior data available in literature and performed a gene-based re-sequencing study.

With the first approach, we identified a homozygous missense mutation in the Von Willebrand Factor A Domain Containing 2 (VWA2) gene in WGS data of 17 unrelated EOAD patients from Flanders-Belgium. Mutation screening in extended Flanders-Belgian and European replication cohorts identified additional homozygous and compound heterozygous missense mutations in VWA2 mimicking autosomal recessive inheritance in sporadic AD patients.

With the second approach, we studied the genetic contribution of the matrix metalloproteinases (MMPs) to the etiology of AD. MMP13, previously functionally associated with AD in cultured neuronal cells and AD transgenic mice through the translational regulation of β-site APP cleaving enzyme 1 (BACE1) via the phosphoinositide 3-kinases (PI3K) signaling pathway, was selected as most promising AD candidate gene. In our study, we identified a premature stop codon (PTC) mutation in one control individual and ultra-rare missense mutations in AD patients only.

With this PhD work, we identified VWA2 and MMP13 as novel AD candidate genes. By sharing these results, we aim to trigger genetic replication and functional follow-up studies needed to unravel the exact role of the identified genes in the etiology of AD and to assess the effect of the identified mutations on disease relevant processes. This might ultimately provide the opportunity to identify novel therapeutic targets for drug development.



Link: https://www.uantwerpen.be/nl/overuantwerpen/faculteiten/faculteit-fbd/onderzoek/doctoraatsverdedigen/