title: Neuroprotective Functions for the Histone Deacetylase SIRT6.
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.
authors.affiliation: Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Shai
authors.initials: S
authors.lastname: Kaluski
authors.affiliation: Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Miguel
authors.initials: M
authors.lastname: Portillo
authors.affiliation: The Massachusetts General Hospital Cancer Center and The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Antoine
authors.initials: A
authors.lastname: Besnard
authors.affiliation: Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Stein
authors.affiliation: Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Monica
authors.initials: M
authors.lastname: Einav
authors.affiliation: The Massachusetts General Hospital Cancer Center and The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstrasse 19, 04103 Leipzig, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Ueberham
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstrasse 19, 04103 Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arendt
authors.affiliation: The Massachusetts General Hospital Cancer Center and The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.affiliation: The Massachusetts General Hospital Cancer Center and The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Amar
authors.initials: A
authors.lastname: Sahay
authors.affiliation: Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. Electronic address: toiber@bgu.ac.il.
authors.forename: Debra
authors.initials: D
authors.lastname: Toiber
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001921:Brain / Q000473:pathology; D004249:DNA Damage; D004789:Enzyme Activation; D017353:Gene Deletion; D042822:Genomic Instability; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007858:Learning; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000066829:Neuroprotection; D009928:Organ Specificity; D010641:Phenotype; D010766:Phosphorylation; D055550:Protein Stability; D037761:Sirtuins / Q000172:deficiency / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016875:tau Proteins; C501860:Sirt6 protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D038362:Glycogen Synthase Kinase 3; C516592:SIRT6 protein, human; D037761:Sirtuins
keywords: Alzheimer’s disease; DNA damage; GSK3; SIRT6; Tau; aging