Kaluski Shai, Portillo Miguel, Besnard Antoine, Stein Daniel, Einav Monica, Zhong Lei, Ueberham Uwe, Arendt Thomas, Mostoslavsky Raul, Sahay Amar, Toiber Debra
Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
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.
Cell Rep. 2017 Mar 28;18(13):3052-3062. doi: 10.1016/j.celrep.2017.03.008.
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.
组蛋白去乙酰化酶SIRT6可促进DNA修复，但其活性会随着年龄的增长而下降，同时伴有DNA损伤的积累。此外，SIRT6基因敲除小鼠表现出加速衰老的表型，并过早死亡。在此，我们报告脑特异性SIRT6缺陷小鼠能够存活，但在4月龄时出现行为缺陷，伴有严重的学习障碍。此外，这些小鼠的大脑显示出DNA损伤、细胞死亡以及tau蛋白过度磷酸化的迹象增加，tau蛋白过度磷酸化是几种神经退行性疾病的关键标志。从机制上讲，SIRT6通过增加激酶GSK3α/β的激活来调节tau蛋白的稳定性和磷酸化。最后，阿尔茨海默病患者的SIRT6 mRNA和蛋白水平降低。综上所述，我们的结果表明，SIRT6对于维持大脑中的基因组稳定性至关重要，其缺失会导致毒性tau蛋白的稳定性和磷酸化。因此，SIRT6及其下游信号通路可能是阿尔茨海默病和年龄相关性神经退行性变的治疗靶点。
