Research focus

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 systematically collect large samples of patients and relatives for genetic studies aimed 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 Aβ plaque deposits. We have also shown that select mutations in presenilin 1 (PS1) and APP are actually causing a significant decrease in Aβ40 production, suggesting a loss of function mechanism in AD. In APP, we have identified mutations in the 5’ regulatory region that increase APP expression to levels comparable to those observed in Down syndrome patients. More recently, we have identified progranulin (PGRN) as a second common gene for FTLD in which dominant loss-of-function mutations cause neurodegeneration. We have 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 to further unravel 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, which we recently reported. We will also continue our efforts to identify 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 the 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 have generated knockout and overexpressing PGRN mice. Comparable experiments will be performed in cellular models. Our efforts at understanding the mechanisms of Aβ plaque formation using transgenic mouse models will be broadened to the identification of key proteins involved in the Aβ aggregation.
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