Journal
NEURON
Volume 105, Issue 4, Pages 630-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2019.11.019
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Funding
- NIH [R01 EY014061, R01 AG033082, R01 NS085054, R01AG043930, P01 AG053760, P30 EY022589]
- Ecole Polytechnique Federale de Lausanne
- Swiss Initiative for Systems Biology [51RTP0151019]
- Polish Ministry of Science and Higher Education [1303/MOB/IV/2015/0: Mobilnosc Plus]
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Sirtuin 1 (Sirt1) is a NAD(+)-dependent deacetylase capable of countering age-related neurodegeneration, but the basis of Sirt1 neuroprotection remains elusive. Spinocerebellar ataxia type 7 (SCA7) is an inherited CAG-polyglutamine repeat disorder. Transcriptome analysis of SCA7 mice revealed downregulation of calcium flux genes accompanied by abnormal calcium-dependent cerebellar membrane excitability. Transcription-factor binding-site analysis of downregulated genes yielded Sirt1 target sites, and we observed reduced Sirt1 activity in the SCA7 mouse cerebellum with NAD(+) depletion. SCA7 patients displayed increased poly(ADP-ribose) in cerebellar neurons, supporting poly(ADP-ribose) polymerase-1 upregulation. We crossed Sirt1-overexpressing mice with SCA7 mice and noted rescue of neurodegeneration and calcium flux defects. NAD(+) repletion via nicotinamide riboside ameliorated disease phenotypes in SCA7 mice and patient stem cell-derived neurons. Sirt1 thus achieves neuroprotection by promoting calcium regulation, and NAD(+) dysregulation underlies Sirt1 dysfunction in SCA7, indicating that cerebellar ataxias exhibit altered calcium homeostasis because of metabolic dysregulation, suggesting shared therapy targets.
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