Studying FUS-mediated Familial ALS using a Drosophilia Model

Several amyotrophic lateral sclerosis (ALS) genes have been identified as their mutalion can lead to familial ALS, including two genes encoding RNA processing proteins TDP-43 and fused in sarcoma (FUS). This project is focused on studying FUS since little is known how FUS mutations cause alterations in RNA metabolism and motor neuron degeneration in ALS. We have been one of the first groups reporting the C-terminal nuclear localization sequence of FUS and the co-Iocalization of mutant FUS with stress granules (1-3). Our new unpublished results show that over-expression of FUS in motor neurons caused locomotion deficiency In the transgenic Drosophila lines. We propose to use this Drosophila model to study how FUS causes in vivo toxicity and motor function deficiency in familial ALS. Four Specific Aims are designed to determine the pathological features of the disease, identify the critical factors contributing to ALS pathogenesis and progression.