@article{c652ff0734404781a98994843077e468,
title = "Nicotinamide Pathway-Dependent Sirt1 Activation Restores Calcium Homeostasis to Achieve Neuroprotection in Spinocerebellar Ataxia Type 7",
abstract = "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.",
keywords = "NAD, Purkinje neuron, calcium, cerebellum, neurodegeneration, neuronal excitability, neuroprotection, potassium channel, sirtuin, spinocerebellar ataxia",
author = "Stoyas, {Colleen A.} and Bushart, {David D.} and Switonski, {Pawel M.} and Ward, {Jacqueline M.} and Akshay Alaghatta and Tang, {Mi bo} and Chenchen Niu and Mandheer Wadhwa and Haoran Huang and Alex Savchenko and Karim Gariani and Fang Xie and Delaney, {Joseph R.} and Terry Gaasterland and Johan Auwerx and Shakkottai, {Vikram G.} and {La Spada}, {Albert R.}",
note = "Funding Information: We are grateful to J. Olefsky (UCSD) for Sirt1 transgenic mice; J. Cleary, F. Fitzgerald, and L. Ranum (Center for NeuroGenetics, University of Florida) and M. Perkins (University of Michigan Brain Bank) for post-mortem materials; and M. Mercola (Stanford) for comments and equipment use. This work was supported by the NIH ( R01 EY014061 to A.R.L.S., R01 AG033082 to A.R.L.S., R01 NS085054 to V.G.S., R01AG043930 to J.A., P01 AG053760 to the University of Michigan, and P30 EY022589 to UCSD), {\'E}cole Polytechnique F{\'e}d{\'e}rale de Lausanne (to J.A.), and the Swiss Initiative for Systems Biology ( 51RTP0-151019 to J.A.). P.M.S. was supported by a mobility grant from the Polish Ministry of Science and Higher Education ( 1303/MOB/IV/2015/0: Mobilnosc Plus ). Funding Information: We are grateful to J. Olefsky (UCSD) for Sirt1 transgenic mice; J. Cleary, F. Fitzgerald, and L. Ranum (Center for NeuroGenetics, University of Florida) and M. Perkins (University of Michigan Brain Bank) for post-mortem materials; and M. Mercola (Stanford) for comments and equipment use. This work was supported by the NIH (R01 EY014061 to A.R.L.S. R01 AG033082 to A.R.L.S. R01 NS085054 to V.G.S. R01AG043930 to J.A. P01 AG053760 to the University of Michigan, and P30 EY022589 to UCSD), ?cole Polytechnique F?d?rale de Lausanne (to J.A.), and the Swiss Initiative for Systems Biology (51RTP0-151019 to J.A.). P.M.S. was supported by a mobility grant from the Polish Ministry of Science and Higher Education (1303/MOB/IV/2015/0: Mobilnosc Plus). A.R.L.S. and V.G.S. provided the conceptual framework. C.A.S. D.D.B. J.M.W. P.M.S. A.S. T.G. J.A. V.G.S. and A.R.L.S. designed the experiments. C.A.S. D.D.B. J.M.W. P.M.S. A.A. M.-b.T. H.H. K.G. J.R.D. C.N. A.S. F.X. T.G. V.G.S. and A.R.L.S. performed the experiments. C.A.S. D.D.B. V.G.S. and A.R.L.S. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2020",
month = feb,
day = "19",
doi = "10.1016/j.neuron.2019.11.019",
language = "English (US)",
volume = "105",
pages = "630--644.e9",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "4",
}