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

doi:10.1016/j.neuron.2019.11.019

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.

Authors

Colleen A Stoyas¹, David D Bushart², Pawel M Switonski³, Jacqueline M Ward⁴, Akshay Alaghatta¹, Mi-Bo Tang⁵, Chenchen Niu¹, Mandheer Wadhwa¹, Haoran Huang⁶, Alex Savchenko⁴, Karim Gariani⁷, Fang Xie⁴, Joseph R Delaney¹, Terry Gaasterland⁸, Johan Auwerx⁷, Vikram G Shakkottai⁹, Albert R La Spada¹⁰

Affiliations

¹ Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA.
² Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14 Str., 61-704 Poznan, Poland.
⁴ Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
⁵ Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Neurology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000 Henan, China.
⁶ Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
⁷ Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
⁸ Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁹ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: vikramsh@med.umich.edu.
¹⁰ Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA; Duke Center for Neurodegeneration and Neurotherapeutics, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: al.laspada@duke.edu.

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.

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

Substances

Niacinamide
Sirt1 protein, mouse
Sirtuin 1
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding