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Defining the Molecular Pathogenesis of the Neurodegenerative Disease Spinoecerebellar Ataxia Type 7


Sirtuin 1 (Sirt1) is a NAD+-dependent protein deacetylase with established effects in countering age-related diseases, including neurodegeneration, yet the basis for Sirt1 neuroprotection remains elusive. Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder in which CAG-polyglutamine (polyQ) repeat expansions in the ataxin-7 gene produce cerebellar degeneration in affected human patients. As transcription dysregulation likely contributes to SCA7 pathogenesis, we performed transcriptome analysis on SCA7 mice, observed downregulation of genes controlling calcium flux, and documented abnormal calcium-dependent membrane excitability in both SCA7 mouse cerebellum and SCA7 patient-derived neuronal cells. Transcription factor binding site analysis of SCA7 down-regulated genes revealed sites for peroxisome proliferator-activated receptors, which are known Sirt1 targets, and we detected marked cerebellar changes in NAD+ metabolism that are known to reduce Sirt1 function. We then crossed Sirt1 transgenic mice with two different SCA7 mouse models, and observed amelioration of cerebellar neurodegeneration, calcium flux defects, and membrane excitability in Sirt1-SCA7 bigenic mice. Finally we detected a direct functional interaction between Sirt1 and Atxn7 protein, which persisted in the presence of polyQ-expanded Atxn7 and correlated with increased turnover of Sirt1. These findings indicate that Sirt1 achieves neuroprotection by promoting proper calcium regulation, reinforce an emerging view that cerebellar ataxias exhibit altered calcium homeostasis due to metabolic dysregulation, and suggest a normal role for a Sirt1-Atxn7 interaction that is perturbed in SCA7.

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