Neuroprotective Functions for the Histone Deacetylase SIRT6

Publication date: 28 March 2017
Source:Cell Reports, Volume 18, Issue 13
Author(s): Shai Kaluski, Miguel Portillo, Antoine Besnard, Daniel Stein, Monica Einav, Lei Zhong, Uwe Ueberham, Thomas Arendt, Raul Mostoslavsky, Amar Sahay, Debra Toiber
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.

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Teaser

Kaluski et al. show that lack of SIRT6 in the brain provokes neurodegeneration by increasing DNA damage, apoptosis, and toxic Tau phosphorylation. DNA damage or lack of SIRT6 activates GSK3, resulting in Tau phosphorylation and stability. GSK3 inhibition rescues this phenotype. Importantly, AD patients show reduced SIRT6 in the brain.


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