Opposing Effects of Sirtuins on Neuronal Survival SIRT1-Mediated Neuroprotection Is Independent of Its Deacetylase Activity 英文参考文献.docVIP

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Opposing Effects of Sirtuins on Neuronal Survival SIRT1-Mediated Neuroprotection Is Independent of Its Deacetylase Activity 英文参考文献.doc

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Opposing Effects of Sirtuins on Neuronal Survival SIRT1-Mediated Neuroprotection Is Independent of Its Deacetylase Activity 英文参考文献

OpposingEffectsofSirtuinsonNeuronalSurvival:SIRT1- MediatedNeuroprotectionIsIndependentofIts DeacetylaseActivity JasonA.Pfister.,ChiMa.,BradE.Morrison,SantoshR.D’Mello* DepartmentofMolecularandCellBiology,UniversityofTexasatDallas,Richardson,Texas,UnitedStatesofAmerica Abstract Background:Growingevidencesuggeststhatsirtuins,afamilyofsevendistinctNAD-dependentenzymes,areinvolvedin the regulation of neuronal survival. Indeed, SIRT1 has been reported to protect against neuronal death, while SIRT2 promotesneurodegeneration.TheeffectofSIRTs3–7ontheregulationofneuronalsurvival,ifany,hasyettobereported. Methodology and Principal Findings: We examined theeffect of expressing each ofthe seven SIRT proteins in healthy cerebellar granule neurons (CGNs) or in neurons induced to die by low potassium (LK) treatment. We report that SIRT1 protectsneuronsfromLK-inducedapoptosis,whileSIRT2,SIRT3andSIRT6induceapoptosisinotherwisehealthyneurons. SIRT5isgenerallylocalizedtoboththenucleusandcytoplasmofCGNsandexertsaprotectiveeffect.Inasubsetofneurons, however,SIRT5localizestothemitochondriaandinthiscaseitpromotesneuronaldeath.Interestingly,theprotectiveeffect of SIRT1 in neurons is not reduced by treatments with nicotinamide or sirtinol, two pharmacological inhibitors of SIRT1. Neuroprotection was also observed with two separate mutant forms of SIRT1, H363Y and H355A, both of which lack deacetylaseactivity.Furthermore,LK-inducedneuronaldeathwasnotpreventedbyresveratrol,apharmacologicalactivator ofSIRT1,atconcentrationsatwhichitactivatesSIRT1.WeextendedouranalysistoHT-22neuroblastomacellswhichcanbe inducedtodiebyhomocysteicacidtreatment.WhiletheeffectsofmostoftheSIRTproteinsweresimilartothatobserved inCGNs,SIRT6wasmodestlyprotectiveagainsthomocysteicacidtoxicityinHT-22cells.SIRT5wasgenerallylocalizedinthe mitochondriaofHT-22cellsandwasapoptotic. Conclusions/Significance:Overall,ourstudymakesthreecontributions-(a)itrepresentsthefirstanalysisofSIRT3–7inthe regulation of neuronal survival,