The goal of this study is to understand molecular basis for genetic and clinical heterogeneity of TDP-43 proteinopathy and to identify genes interacting with TDP-43 that may modify clinical outcomes of TDP-43 proteinopathy. TDP-43 positive neuropathology has been found in a wide range of diseases, including frontotemporal lobar degeneration (FTLD), Alzheimer s disease and amyotrophic lateral sclerosis (ALS) among others. Recent studies have revealed genetic mutations in RNA-binding protein TDP-43 in patients with ALS, although the majority of patients with TDP-43 proteinopathy do not have detectable TDP-43 mutations. These findings highlight the complexity and heterogeneity of TDP-43 proteinopathy. To study biological function and pathological roles of TDP-43, we have established a range of in vitro biochemical, molecular and cell biological assays to examine the wild type TDP-43 function and effects of ALS-associated TDP-43 mutations. Using transgenic flies expressing human TDP-43, we have established a Drosophila model that recapitulates a number of neuropathological and clinical features of TDP-43 proteinopathy. We have begun to use a combined approach to identify factors interacting with TDP-43 and begun to construct signaling pathways/networks that TDP-43 is involved in. We propose to systematically search for genes interacting with TDP-43 and to identify genetic modifiers of TDP-43 proteinopathy using our transgenic fly model. Our work will not only help elucidate pathogenic mechanisms underlying this disease but also suggest future therapeutic targets specific to TDP-43-dependent signaling pathways.
TDP-43 proteinopathy is a group of common neurodegenerative disorders, including dementia and motor neuron diseases such as ALS. Genetics and clinical manifestations of TDP-43 proteinopathy are highly heterogeneous. To study this devastating disease, we have established cell culture assays and a transgenic fly model. Based on published work and our preliminary studies, we propose to use a combined molecular, biochemical, cell biological and animal model approach to identify factors that contribute to pathogenesis of TDP-43 proteinopathy and genes that modify the clinical manifestations of affected patients. Our proposed work will not only help elucidate molecular mechanisms underlying this disease but also suggest future therapeutic targets specific to TDP-43- dependent signaling pathways.
