Cell Signaling and Neurodegeneration

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DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is one of nine fatal inherited neurodegenerative diseases caused by expansion of an inframe CAG trinucleotide repeat. Each repeat tract encodes a stretch of glutamine residues in the affected protein, in the case of SCA1 the protein is ataxin-1 (ATXN1). Symptoms of SCA1 include loss of motor coordination and balance, slurred speech, swallowing difficulty, spasticity, and some cognitive impairment. A characteristic feature of SCA1 pathology is atrophy and eventual loss of Purkinje cells from the cerebellar cortex. Like many neurodegenerative disorders, SCA1 is typically a late onset disease suggesting that physiological changes due to aging contribute to the onset of the disease. There is currently no effective treatment. Thus, identifying signaling pathways and cellular mediators of SCA1 onset and progression remain a application for continued support. The major aims of this competitive renewal, are: 1) dissecting the signaling pathway(s) and their components that regulate phosphorylation of ATXN1-S776 in cerebellar Purkinje cells in vivo, and 2) assessing whether S776 and its phosphorylation plays a role in mutant ATXN1-induced disease in regions of the brain in addition to Purkinje cells. Most notably the Bulbar signs affecting swallowing, due to pathology in the brainstem