The Role And Mechanism Of SIRT6 In Neuronal Oxidative Stress Damage And In Neural Stem Cell Property Regulation

Ischemic stroke is a life-threatening disease with high mortality,high disability and high recurrence.Caloric restriction,resveratrol,and ischemic preconditioning have been shown to protect against ischemic injury in the brain as well as in the other tissues,among which the Silent Information Regulator(SIRT)family plays a vital role.Sirtuins are involved in the regulation of metabolism,stress response,inflammation and apoptosis,etc,and all of these are the key factors leading to brain damage after cerebral ischemia.The expression and activity of sirtuins are associated with the cerebral protective role of multiple genes,drugs and therapeutic treatments,however,whether sirtuins are directly implicated in ischemic protection remains unclear.In this study,we explore the role of SIRT6,a member of sirtuin family,in cerebral ischemia and the underlying mechanisms.In the first chapter,we analyze the expression of SIRT6 in the adult mouse brain.Under physiological conditions,SIRT6 is mainly expressed in cortical and striatal neurons with predominant nuclear localization,and there is no detectable level of SIRT6 in the subventricular zone.Then mice are subjected to transient middle cerebral artery occlusion(tMCAO)surgery for stroke model.During the acute phase of ischemia-reperfusion,SIRT6 is downregulated in the penumbra neurons,but upregulated in the penumbra reactive astrocytes with unexpected cytoplasmic localization.During the subacute phase of ischemia-reperfusion,SIRT6 expression is increased in the neural stem cells of the subventricular zone and is also observed in the neuroblasts.In the second chapter,we treat SH-SY5 Y cells with hydrogen to serve as an in vitro model for the neuronal injury after cerebral ischemia.Overexpression of SIRT6 leads to decreased cell viability and increased necrotic cell death as well as reactive oxygen species production under oxidative stress.Mechanistic study reveals that SIRT6 could increase autophagy-mediated neuronal cell damage via attenuation of AKT signaling pathway.In the third chapter,we study the effect of SIRT6 on neural stem cell character regulation.SIRT6 is able to enhance neural stem cell proliferation and self-renewal capacity,and also promote the astroglial differentiation.Furthermore,SIRT6 upregulates notch receptors and ligands expression,prevents notch intracellular domain(NICD)from proteasomal degradation,and interacts with NICD to enhance its transcriptional activity,thus contributing to the stemness maintenance through induction of notch signaling pathway.In summary,we report a cell-type specific change in SIRT6 expression after cerebral ischemia.Downregulation of SIRT6 in the peri-infarct neurons might be a stress response to protect against ischemic injury;while upregulation of SIRT6 in the SVZ neural stem cells might influence the stroke-induced neurogenesis.These results indicate the diverse role of SIRT6 after cerebral ischemia,providing a potential therapeutic target for clinical stroke treatment.