Nicotinamide Pathway-Dependent Sirt1 Activation Restores Calcium Homeostasis to Achieve Neuroprotection in Spinocerebellar Ataxia Type 7

Colleen A. Stoyas, David D. Bushart, Pawel M. Switonski, Jacqueline M. Ward, Akshay Alaghatta, Mi bo Tang, Chenchen Niu, Mandheer Wadhwa, Haoran Huang, Alex Savchenko, Karim Gariani, Fang Xie, Joseph R. Delaney, Terry Gaasterland, Johan Auwerx, Vikram G. Shakkottai, Albert R. La Spada

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)630-644.e9
JournalNeuron
Volume105
Issue number4
DOIs
StatePublished - Feb 19 2020
Externally publishedYes

Keywords

  • NAD
  • Purkinje neuron
  • calcium
  • cerebellum
  • neurodegeneration
  • neuronal excitability
  • neuroprotection
  • potassium channel
  • sirtuin
  • spinocerebellar ataxia

ASJC Scopus subject areas

  • Neuroscience(all)

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