Cell Signaling and Neurodegeneration

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DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is an untreatable fatal autosomal dominant neurodegenerative disorder caused by the expansion of a glutamine repeat within the SCA1-encoded protein ATXN1. Previous work showed that ATXN1 is modified by phosphorylation at serine residue 776 and this phosphorylation is critical for mutant ATXN1 to cause disease. Recent evidence form the parent project indicates that PKA mediates the phosphorylation of serine 776. This application, in response to Notice Number (NOT-OD-09-058), "NIH Announces the Availability of Recovery Act Funds for Competitive Revisions Applications" is a request to undertake a high-throughput screen and lead compound optimization for inhibitors of PKA-mediated phosphorylation of serine 776.