Spinocerebellar ataxia type 1 (SCA1) is one of nine fatal inherited neurodegenerative diseases caused by expansion of an in-frame 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 major challenge in the search for therapeutics and is the focus of the research outlined in this application for continued support. The major aims of this competitive renewal are to further examine the role of ATXN1-S776 phosphorylation by examining the impact of altering ATXN1-S776 phosphorylation on polyQexp ATXN1 toxicity the brainstem-medulla, and characterize a novel protective pathway activated by a cholecystokinin receptor 1 (Cck1R) agonist in SCA Purkinje cells.
We hypothesize that phosphorylation of S776 (residue number based on human ATXN1 with 30Q), is a target for therapeutic development. One aim will be to examine the extent to which the pS776 pathway contributes to SCA1 disease in regions of the brain beyond the cerebellum, i.e. does S776 have role in the SCA1 premature lethality phenotype in addition to the cerebellar ataxia? The second aim is characterize a novel protective pathway activated by a cholecystokinin receptor 1 (Cck1R) agonist in SCA Purkinje cells as an important step towards drug development.
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