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

Neuron. 2020 Feb 19;105(4):630-644.e9. doi: 10.1016/j.neuron.2019.11.019. Epub 2019 Dec 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / physiology*
  • Cell Line
  • Cerebellum / metabolism
  • Female
  • Homeostasis / physiology*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuroprotection / physiology*
  • Niacinamide / metabolism*
  • Organ Culture Techniques
  • Signal Transduction / physiology
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Spinocerebellar Ataxias / genetics
  • Spinocerebellar Ataxias / metabolism*
  • Spinocerebellar Ataxias / prevention & control


  • Niacinamide
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Calcium