Regulation of LRRK2 Stability by the E3 Ubiquitin Ligase CHIP 英文参考文献.docVIP

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Regulation of LRRK2 Stability by the E3 Ubiquitin Ligase CHIP 英文参考文献.doc

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Regulation of LRRK2 Stability by the E3 Ubiquitin Ligase CHIP 英文参考文献

RegulationofLRRK2StabilitybytheE3UbiquitinLigase CHIP XiaodongDing1,MatthewS.Goldberg1,2* 1DepartmentofNeurology,TheUniversityofTexasSouthwesternMedicalCenter,Dallas,Texas,UnitedStatesofAmerica,2DepartmentofPsychiatry,TheUniversityof TexasSouthwesternMedicalCenter,Dallas,Texas,UnitedStatesofAmerica Abstract Dominantlyinheritedmutationsintheleucine-richrepeatkinase2gene(LRRK2)arethemostcommoncauseoffamilial Parkinson’sdisease(PD)andhavealsobeenidentifiedinindividualswithsporadicPD.Althoughtheexactcellularfunction ofLRRK2remainsunknown,mostPD-linkedmutationsappeartobetoxictocellsincultureviamechanismsthatdependon thekinaseactivityofLRRK2orontheformationofcytoplasmicinclusions.HereweshowthattheE3ubiquitinligaseCHIP physically associates with LRRK2 and regulates the cellular abundance of LRRK2. We further show that LRRK2 forms a complexwithoverexpressedandendogenousCHIPandHsp90.OurdataindicatesthatthedestabilizationofLRRK2byCHIP isduetoubiquitinationandproteasome-dependentdegradation.Hsp90canattenuateCHIP-mediateddegradationandthis canbeblockedbytheHsp90inhibitorgeldanamycin.Thesefindingsprovideimportantinsightintothecellularregulation ofLRRK2stabilityandmayleadtothedevelopmentoftherapeuticstotreatPDbasedoncontrollingLRRK2stability. Citation:DingX,GoldbergMS(2009)RegulationofLRRK2StabilitybytheE3UbiquitinLigaseCHIP.PLoSONE4(6):e5949.doi:10.1371/journal.pone.0005949 Editor:MarkR.Cookson,NationalInstitutesofHealth,UnitedStatesofAmerica ReceivedDecember26,2008;AcceptedApril27,2009;PublishedJune17,2009 Copyright: ? 2009 Ding, Goldberg. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited. Funding: Funding tosupport thisresearch was provided bythe Crowley Foundation.The funders had norolein study design, datacollectionand analysis, decisiontopublish,orpreparationofthemanuscript. CompetingInterests:Theauthorsh