Novel chaperones and neurodegeneration

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Abstract The polyglutamine (polyQ) diseases are a class of nine neurodegenerative diseases caused by the expansion of a polyQ tract in specific proteins. Expansion of the polyQ tract results in protein aggregation and neurodegeneration. Currently there are no curative treatments for the polyQ diseases. One potential therapy for the polyQ diseases is the development of strategies to reduce polyQ aggregation. Interestingly we and others have found that one organism, Dictyostelium discoideum, is naturally resist to polyQ aggregation. Further work from our laboratory has identified a novel molecular chaperone we named serine rich chaperone protein 1 (SRCP1) that is both necessary for Dictyostelium’s resistance to polyQ aggregation and sufficient to impart resistance to polyQ aggregation to other organisms. In this application we propose to 1) determine the molecular mechanism SRCP1 utilizes to recognize polyQ expanded proteins and suppress their aggregation; 2) determine if SRCP1 can suppress protein aggregation and behavioral deficits in a mouse model of Huntington’s disease; and 3) determine if SRCP1 is capable of suppressing polyQ aggregation in a mouse model of Spinocerebellar ataxia type 3. Together these studies will determine the mechanism SRCP1 utilizes to suppress polyQ aggregation and determine if SRCP1 has the ability to prevent or reverse disease phenotypes in mouse models of polyQ disease. !