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. Identifying signaling pathways and cellular mediators of SCA1 pathogenesis in the cerebellum leading to ataxia and in the brainstem that underlie lethality are critical in the search for therapeutics and are the focus of the research outlined in this application for continued support.
A challenge facing understanding pathogenesis of SCA1, and neurodegenerative diseases in general, is elucidating the relative contribution of each molecular pathway altered has in pathogenesis in the different regions of the brain affected. We will - 1) assess relative contributions of a) a gain-of- CIC function, and the ATXN1/Rbm17 complex have in Purkinje cell SCA1 disease; 2) assess the extent to which the SCA1 Purkinje cell pathogenic pathway drives disease outside of the cerebellum, focusing on the brainstem; 3) use RNA-seq to profile brainstem (medulla) transcriptome and identify changes correlating with lethality in Sca1154Q/2Q mice.
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