Gladstone Institute

High-throughput Screens in Yeast to Identify Therapies for Parkinson’s Disease

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I am interested in understanding the mechanisms of toxicity of a small protein, alpha-synuclein, implicated in a number of neurological disorders, the most common of which is Parkinson’s disease (PD). Initially, I am conducting my studies in the baker’s yeast, a unicellular organism which has proven useful in the past for elucidating the basic mechanisms of human diseases. Subsequently, I will validate these studies in mammalian cells, which constitute a more physiologically relevant system. My first experimental model is genetically engineered “humanized” yeast that exhibits relevant features of alpha-synuclein physiology and pathology. Taking advantage of the availability of collections of a large number of yeast mutants and chemically diverse molecules, and the tractability of yeast cells, I am conducting genetic and pharmacologic screens to identify genes and small molecules that modulate the cellular toxicity of alpha-synuclein.

Whereas genetic studies are valuable to understand the molecular mechanisms underlying toxicity, pharmacologic approaches can disclose lead compounds with potential therapeutic properties. These studies are complementary since genes that modulate the toxicity of alpha-synuclein may represent attractive therapeutic targets, whereas understanding the mode of action of bioactive molecules may help to elucidate pathogenic mechanisms of disease. Ultimately, I will test the efficacy of these genes and compounds to modulate alpha-synuclein toxicity in mammalian cells. Using these approaches, I expect to identify putative drug targets and bioactive molecules that might serve for the development of preventive or protective therapies for PD and other neurological disorders associated with alpha-synuclein.