PGC-1alpha Down-Regulation Affects the Antioxidant Response in Friedreichs Ataxia 英文参考文献.docVIP

PGC-1alphaDown-RegulationAffectstheAntioxidant ResponseinFriedreich’sAtaxia DanieleMarmolino1,MarioManto1,2,FabioAcquaviva3,PaolaVergara3,AjayRavella1 ,Antonella Monticelli4,MassimoPandolfo1* 1LaboratoiredeNeurologieExpe′rimentale,Universite′LibredeBruxelles(ULB),Brussels,Belgium,2FondsNationaldelaRechercheScientifique(FNRS),Brussels,Belgium, 3DepartmentofCellularandMolecularBiology,UniversityofNaples‘‘FedericoII’’,Naples,Italy,4IEOS,ConsiglioNazionaledelleRicerche(CNR),Naples,Italy Abstract Background: Cells from individuals with Friedreich’s ataxia (FRDA) show reduced activities of antioxidant enzymes and cannotup-regulatetheirexpressionwhenexposedtooxidativestress.Thisbluntedantioxidantresponsemayplayacentral role in the pathogenesis. We previously reported that Peroxisome Proliferator Activated Receptor Gamma (PPARc) Coactivator1-alpha(PGC-1a),atranscriptionalmasterregulatorofmitochondrialbiogenesisandantioxidantresponses,is down-regulatedinmostcelltypesfromFRDApatientsandanimalmodels. Methodology/Principal Findings: We used primary fibroblasts from FRDA patients and the knock in-knock out animal modelforthedisease(KIKOmouse)todeterminebasalsuperoxidedismutase2(SOD2)levelsandtheresponsetooxidative stressinducedbytheadditionofhydrogenperoxide.Wemeasuredthesameparametersafterpharmacologicalstimulation of PGC-1a. Compared to control cells, PGC-1a and SOD2 levels were decreased in FRDA cells and did not change after addition of hydrogen peroxide. PGC-1a direct silencing with siRNA in control fibroblasts led to a similar loss of SOD2 responsetooxidativestressasobservedinFRDAfibroblasts.PGC-1aactivationwiththePPARcagonist(Pioglitazone)or with a cAMP-dependent protein kinase (AMPK) agonist (AICAR) restored normal SOD2 induction. Treatment of the KIKO micewithPioglitazonesignificantlyup-regulatesSOD2incerebellumandspinalcord. Conclusions/Significance:PGC-1adown-regulationislikelytocontributetothebluntedantioxidantresponseobservedin cellsfromFRDApatients.Thisresponseca