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Organisation

VIB CMN - Neurodegenerative Brain Diseases Group

Research Group

Lifecycle:1 Oct 2003  →  Today
Organisation profile:Our focus is on genetics, genomics and neuropathology of the neurodegenerative brain diseases Alzheimer's disease (AD), frontal temporal lobar degeneration (FTLD) and Parkinson's disease (PD), attempting to find molecular mechanisms of protein aggregation in dementia. We systematical collect large samples of patients and relatives for genetic studies aiming at identifying disease genes using either a positional cloning strategy in multiplex families or association studies in patient/control groups. Novel key proteins that are potential drug targets for more effective treatment are analyzed in cellular and mouse models. Using this integrated approach we have already made several major contributions to AD with the identification of the Flemish and Austrian mutations in the amyloid precursor protein gene (APP) that have highlighted the relationship between neuronal and vascular components of AD pathology as well as of different Aß plaque deposits. We also showed that select mutations in presenilin 1 (PS1) and APP are actually causing a significant decrease of Aß40 production suggesting a loss of function mechanism in AD. And we identified in APP mutations in the 5' regulatory region that increase APP expression to levels comparable to that observed in Down syndrome patients. More recently we identified progranulin (PGRN) as a second common gene for FTLD in which dominant loss-of-function mutations cause neurodegeneration. We also demonstrated genetic and clinical heterogeneity with PGRN contributing to FTLD, AD, PD as well as amyotrophic lateral sclerosis (ALS).In our current research we aim at further unraveling genetic heterogeneity by identifying novel chromosomal loci and by mapping the underlying genes for AD at 7q36 and for dementia with Lewy bodies at 2q35-q36 that we recently reported. Also, we will continue our efforts at identifying the genetic modifying factor that contributes to the highly variable onset ages in PGRN mutation carriers. The extended patient and control groups will be used for genetic association studies to unravel spectrum of genetic factors that contribute to risk for these diseases. In these groups, we are investing in the collection of biosamples for proteomics and QTL mapping of endophenotypic disease markers. To elucidate the mechanism of neurodegeneration due to loss-of-function mutations in PGRN, we generated knockout and overexpressing PGRN mice. Comparable experiments will be done in cellular models. Our efforts in understanding the mechanisms of Aß plaque formation using transgenic mouse models will be broadened to the identification of key proteins that are involved in the Aß aggregation.
Keywords:ALZHEIMER'S DISEASE, FRONTOTEMPORAL DEMENTIA, MOUSE TRANSGENESIS, NEURODEGENERATIVE BRAIN DISEASES, DEMENTIA, PARKINSONS DISEASE, MOLECULAR GENETICS, CELLULAR MODELSYSTEMS
Disciplines:Genetics, Systems biology, Biomaterials engineering, Biological system engineering, Biomechanical engineering, Other (bio)medical engineering, Environmental engineering and biotechnology, Industrial biotechnology, Other biotechnology, bio-engineering and biosystem engineering, Molecular and cell biology, Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing