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泛在计算系统研究中心学术报告会

报告题目：Genetic screens provide insight into Parkinson’s disease and other neurodegenerative disease mechanisms

时间：2019年11月25日（周一）上午10：00-11：30

地点：计算所446会议室

报告人：Aaron D. Gitler 教授, Stanford University

摘要：

My goal is to discover the cellular and molecular mechanisms by which protein aggregates contribute to neurodegeneration and to harness these mechanisms to devise novel therapeutic strategies. We use the baker’s yeast, Saccharomyces cerevisiae, as a simple, yet powerful model system to study the cell biology underpinning protein-misfolding diseases, which include Alzheimer’s disease, Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). We are focusing on the Parkinson’s disease protein alpha-synuclein and the ALS disease protein TDP-43 and have generated yeast models to define mechanisms by which these proteins cause PD ALS. Because these proteins aggregate and are toxic in yeast, we have used these yeast models to perform high-throughput genomewide modifier screens to discover suppressors and enhancers of toxicity. Launching from the studies in yeast, we have extended our findings into animal models and even recently into human patients. For example, we discovered mutations in one of the human homologs of a hit from our yeast TDP-43 modifier screen in ALS patients. Mutations in this gene are relatively common (~5% of cases) making it one of the most common genetic risk factors for ALS discovered to date. These screens are also providing new and completely unexpected potential drug targets, underscoring the power of such simple model systems to help reveal novel insight into human disease. In our PD studies, we have defined how PD genes and risk factors converge on alpha-synuclein aggregation and prion-like spreading, and validated these findings in mouse neurons, human iPS-derived neurons and in mouse models.