Stoyas, Colleen A.Bushart, David D.Switonski, Pawel M.Ward, Jacqueline M.Alaghatta, AkshayTang, Mi-boNiu, ChenchenWadhwa, MandheerHuang, HaoranSavchenko, AlexGariani, KarimXie, FangDelaney, Joseph R.Gaasterland, TerryAuwerx, JohanShakkottai, Vikram G.La Spada, Albert R.2020-03-112020-03-112020-03-112020-02-1910.1016/j.neuron.2019.11.019https://infoscience.epfl.ch/handle/20.500.14299/167184WOS:000514829900009Sirtuin 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.NeurosciencesNeurosciences & Neurologymouse modelcerebellar-ataxiadisease progressionmutant ataxin-7purkinje-cellsmitochondrialmetabolismmicedysfunctionneuronstext::journal::journal article::research article