Neuroprotective Functions for the Histone Deacetylase SIRT6

• DOI: 10.1016/j.celrep.2017.03.008
• Publication Date: 2017-03-28T17:34:19Z
• Authors: Shai Kaluski; Miguel Portillo; Antoine Besnard; Daniel Stein; Monica Einav; Lei Zhong; Uwe Ueberham; Thomas Arendt; Raul Mostoslavsky; Amar Sahay; Debra Toiber
• Keywords: SIRT6; Histone deacetylase inhibitor; Histone deacetylase 5; HDAC3; HDAC1

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