The Interaction of Ataxin-1 with the RORalpha Complex in SCA1

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DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion within the SCA1-encoded protein ataxin-1. SCA1 is one of a family of nine polyglutamine diseases, including Huntington's disease. As SCA1 progresses, Purkinje cell degeneration causes cerebellar symptoms, including gait abnormalities and loss of coordination. Previous work has shown that proper cerebellar development is coordinated by RORalpha, a nuclear hormone receptor. Furthermore, RORalpha and ataxin-1 interact in vivo and share a common set of signaling targets. Purkinje cell RORalpha levels are decreased in SCA1 mice, but can be rescued by turning off ataxin-1 expression, suggesting a role for RORalpha in the prevention of SCA1 pathogenesis. This goal of this research is to determine whether loss of RORalpha exacerbates the degeneration associated with SCA1, providing new therapeutic targets for this family of neurodegenerative diseases.