Neuroprotective Functions for the Histone Deacetylase SIRT6

Shai Kaluski, Miguel Portillo, Antoine Besnard, Daniel Stein, Monica Einav, Lei Zhong, Uwe Ueberham, Thomas Arendt, Raul Mostoslavsky, Amar Sahay, Debra Toiber

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

The histone deacetylase SIRT6 promotes DNA repair, but its activity declines with age with a concomitant accumulation of DNA damage. Furthermore, SIRT6 knockout mice exhibit an accelerated aging phenotype and die prematurely. Here, we report that brain-specific SIRT6-deficient mice survive but present behavioral defects with major learning impairments by 4 months of age. Moreover, the brains of these mice show increased signs of DNA damage, cell death, and hyperphosphorylated Tau—a critical mark in several neurodegenerative diseases. Mechanistically, SIRT6 regulates Tau protein stability and phosphorylation through increased activation of the kinase GSK3α/β. Finally, SIRT6 mRNA and protein levels are reduced in patients with Alzheimer's disease. Taken together, our results suggest that SIRT6 is critical to maintain genomic stability in the brain and that its loss leads to toxic Tau stability and phosphorylation. Therefore, SIRT6 and its downstream signaling could be targeted in Alzheimer's disease and age-related neurodegeneration.

Original languageEnglish
Pages (from-to)3052-3062
Number of pages11
JournalCell Reports
Volume18
Issue number13
DOIs
StatePublished - 28 Mar 2017

Keywords

  • Alzheimer's disease
  • DNA damage
  • GSK3
  • SIRT6
  • Tau
  • aging

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)

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