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.