Development of a Knock-in Mouse Model for Spinocerebellar Ataxia Type 3

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DESCRIPTION (provided by applicant): This R03 proposal seeks to develop and the first knock-in mouse model of the polyglutamine (polyQ) neurodegenerative disease, Spinocerebellar Ataxia type 3 (SCA3). SCA3 is the most common dominantly inherited ataxia in the United States and many regions of the world, and is the second most common neurodegenerative disease caused by a polyglutamine-encoding CAG repeat expansion. In SCA3 this expansion encodes an abnormally long stretch of the amino acid glutamine in the disease protein, the de- ubiquitinating enzyme (DUB) ataxin-3. Remarkably, while much has been learned about SCA3 pathogenesis, no one has yet developed a knock-in mouse model of SCA3. In other polyglutamine diseases, knock-in models have led to fundamental insights into disease mechanisms and have begun to identify potential drug therapies for specific polyglutamine diseases. The current studies will build on our recent success targeting a human CAG repeat expansion into the murine Atxn3 locus, resulting in mice that express polyQ-expanded (pathogenic) ataxin-3. The overall hypothesis is that the resultant Atxn3 (Q82) knock-in mouse will successfully model molecular features of SCA3 and shed light on disease mechanisms. Our primary goal is to fully develop and characterize this model so that it can be made available as quickly as possible to the broader research community, though we also anticipate making discoveries that contribute to a better understanding of disease mechanisms in this polyglutamine disease. This two year R03 proposal has a single aim: to complete the development and characterization of a knock-in mouse model of SCA3. A series of behavioral, immunohistochemical, molecular and neuropathological analyses will be performed in SCA3 knock-in mice. These studies will be complemented by innovative methods of analysis that take advantage of our lab's expertise in ataxin-3 and ubiquitin biochemistry, polyglutamine-specific methods, and electrophysiology. Impact: No therapies exist for SCA3, a devastating and fatal disease, and the basic disease mechanism remains poorly understood. As the most common dominantly inherited ataxia and the second most common polyglutamine disease, SCA3 lags behind other polyQ diseases in not having a knock-in model. The knock-in model characterized here will provide researchers with the first genetically precise SCA3 model, which will greatly facilitate the study of molecular mechanisms and potential therapeutic strategies. Our laboratory's expertise in the wide range of techniques employed to characterize this line, together with our knowledge of newly recognized properties of the SCA3 disease protein, ataxin-3, also place us in an excellent position to mine this novel model for significant clues to SCA3 disease pathogenesis. PUBLIC HEALTH RELEVANCE: The studies proposed here will generate and characterize the first knock-in mouse model of the polyglutamine (polyQ) neurodegenerative disease, Spinocerebellar ataxia (SCA3). They will provide researchers with a genetically and physiologically precise SCA3 model in which to investigate disease mechanisms and test therapeutic strategies.