DJ-1 Modulates α-Synuclein Aggregation State in a Cellular Model of Oxidative Stress Relevance for Parkinsons Disease and Involvement of HSP70 英文参考文献.docVIP

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DJ-1 Modulates α-Synuclein Aggregation State in a Cellular Model of Oxidative Stress Relevance for Parkinsons Disease and Involvement of HSP70 英文参考文献.doc

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DJ-1 Modulates α-Synuclein Aggregation State in a Cellular Model of Oxidative Stress Relevance for Parkinsons Disease and Involvement of HSP70 英文参考文献

DJ-1Modulatesa-SynucleinAggregationStateina CellularModelofOxidativeStress:Relevancefor Parkinson’sDiseaseandInvolvementofHSP70 SaraBatelli1.,DiegoAlbani1.*,RaffaelaRametta2,LetiziaPolito1,FrancescaPrato1,MarziaPesaresi1, AlessandroNegro3,GianluigiForloni1 1DepartmentofNeuroscience,‘‘MarioNegri’’InstituteforPharmacologicalResearch,Milan,Italy,2DepartmentofInternalMedicine,OspedalePoliclinico,Mangiagallie ReginaElenaFondazioneIRCCS,Universita` diMilano,Milano,Italy,3DepartmentofBiochemistry,Universita` diPadova,Padova,Italy Abstract Background:Parkinson’sdisease(PD)isaneurodegenerativepathologywhosemolecularetiopathogenesisisnotknown. Novel contributions have come from familial forms of PD caused by alterations in genes with apparently unrelated physiologicalfunctions.Thegenecodingforalpha-synuclein(a-syn)(PARK1)hasbeeninvestigatedasa-synislocatedin Lewybodies(LB),intraneuronalinclusionsinthesubstantianigra(SN)ofPDpatients.A-synhasneuroprotectivechaperone- likeandantioxidantfunctionsandisinvolvedindopaminestorageandrelease.DJ-1(PARK7),anotherfamily-PD-linkedgene causinganautosomalrecessiveformofthepathology,showsantioxidantandchaperone-likeactivitiestoo. Methodology/PrincipalFindings:Thepresentstudyaddressedthequestionwhethera-synandDJ-1interactfunctionally, withaviewtofindingsomemechanismlinkingDJ-1inactivationanda-synaggregationandtoxicity.Wedevelopedanin vitro model of a-syn toxicity in the human neuroblastoma cell line SK-N-BE, influencing DJ-1 and a-syn intracellular concentrationsbyexogenousadditionofthefusionproteinsTAT-a-synandTAT-DJ-1;DJ-1wasinactivatedbythesiRNA method. On a micromolar scale TAT-a-syn aggregated and triggered neurotoxicity, while on the nanomolar scale it was neuroprotective against oxidative stress (induced by H2O2 or 6-hydroxydopamine). TAT-DJ-1 increased the expression of HSP70,whileDJ-1silencingmadeSK-N-BEcellsmoresusceptibletooxidativechallenge,renderingTAT-a-synneurotoxicat nanomolarscale,withtheappearanceofTAT-a-synaggregates