Involvment of Cytosolic and Mitochondrial GSK-3β in Mitochondrial Dysfunction and Neuronal Cell Death of MPTPMPP+-Treated Neurons 英文参考文献.docVIP

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Involvment of Cytosolic and Mitochondrial GSK-3β in Mitochondrial Dysfunction and Neuronal Cell Death of MPTPMPP+-Treated Neurons 英文参考文献.doc

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InvolvmentofCytosolicandMitochondrialGSK-3βinMitochondrialDysfunctionandNeuronalCellDeathofMPTPMPP-TreatedNeurons英文参考文献

InvolvmentofCytosolicandMitochondrialGSK-3bin MitochondrialDysfunctionandNeuronalCellDeathof MPTP/MPP+-TreatedNeurons Agne`sPetit-Paitel*,Fre′de′ricBrau,JulieCazareth,Joe¨lleChabry InstitutdePharmacologieMole′culaire etCellulaire,CentreNationaldelaRechercheScientifique,Unite′ MixtedeRecherche6097,Valbonne,France Abstract AberrantmitochondrialfunctionappearstoplayacentralroleindopaminergicneuronallossinParkinson’sdisease(PD).1- methyl-4-phenylpyridiniumiodide(MPP ),theactivemetaboliteofN-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP),is + a selective inhibitor of mitochondrial complex I and is widely used in rodent and cell models to elicit neurochemical alterationsassociatedwithPD.RecentfindingssuggestthatGlycogenSynthaseKinase-3b(GSK-3b),acriticalactivatorof neuronal apoptosis, is involved in the dopaminergic cell death. In this study, the role of GSK-3b in modulating MPP - + induced mitochondrial dysfunction and neuronal death was examined in vivo, and in two neuronal cell models namely primaryculturedandimmortalizedneurons.Inbothcellmodels,MPTP/MPP+treatmentcausedcelldeathassociatedwith time-andconcentration-dependentactivationofGSK-3b,evidencedbytheincreasedleveloftheactiveformofthekinase, i.e.GSK-3bphosphorylatedattyrosine216residue.Usingimmunocytochemistryandsubcellularfractionationtechniques, + weshowedthatGSK-3bpartiallylocalizedwithin mitochondriainbothneuronalcellmodels.Moreover,MPP treatment induced a significant decrease of the specific phospho-Tyr216-GSK-3b labeling in mitochondria concomitantly with an + increase into the cytosol. Using two distinct fluorescent probes, we showed that MPP induced cell death through the depolarizationofmitochondrialmembranepotential.InhibitionofGSK-3bactivityusingwell-characterizedinhibitors,LiCl + andkenpaullone,andRNAinterference,preventedMPP -inducedcelldeathbyblockingmitochondrialmembranepotential changesandsubsequentcaspase-9and-3activation.TheseresultsindicatethatGSK-3bisacriticalmediatorofMPTP/M