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Title

Nicotinamide pathway-dependent Sirt1 activation restores calcium homeostasis to achieve neuroprotection in spinocerebellar ataxia type 7

Authors
Stoyas, Colleen A
Bushart, David D
Switonski, Pawel M
Ward, Jacqueline M
Alaghatta, Akshay
Tang, Mi-Bo
Niu, Chenchen
Wadhwa, Mandheer
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Published in Neuron. 2020, vol. 105, no. 4, p. 630-644.e9
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 AnimalsCalcium/physiologyCell LineCerebellum/metabolismFemaleHomeostasis/physiologyHumansMaleMiceMiceInbred C57BLMiceTransgenicNeuroprotection/physiologyNiacinamide/metabolismOrgan Culture TechniquesSignal Transduction/physiologySirtuin 1/genetics/metabolismSpinocerebellar Ataxias/genetics/metabolism/prevention & control
Identifiers
PMID: 31859031
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Research group Laboratoire de recherche NAFLD et résistance à l'insuline (997)
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STOYAS, Colleen A et al. Nicotinamide pathway-dependent Sirt1 activation restores calcium homeostasis to achieve neuroprotection in spinocerebellar ataxia type 7. In: Neuron, 2020, vol. 105, n° 4, p. 630-644.e9. doi: 10.1016/j.neuron.2019.11.019 https://archive-ouverte.unige.ch/unige:143075

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Deposited on : 2020-10-14

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