ThemotordefectsofParkinson"sdiseasearerelatedtothelossofdopaminergicneuronsinspecificbrainregions.ExaminationoftheseneuronsindiseasedtissuehasrevealedthepresenceofLewybodies,denseaggregatesthatincludetheproteinalpha-synuclein.AgeneticbasisformostcasesofParkinson"sdiseasehasnotyetbeenidentified,butmutationsinalpha-synucleinhavebeenassociatedwithatleastonerareformofthedisease,andmutationsinanotherprotein,theparkingene,areassociatedwithanotherinheritedformofParkinson"sdisease.ParkinisfoundinLewybodiesalongwithalpha-synucleinandtheparkinproteinisanE3ubiquitinligase.Parkinappearstoworkinconjuctionwithubiquitinactivating(Uba)1,anE1proteinandtheubiquitin-conjugating(Ubc)enzymesUbcH7&8.TheE1deliversubiquitintotheE2inacyclethatcreatesanincreasingchainofubiquitin.TheParkinE3ligatesthisontosubstratesandsotagstheseproteinsinnormalcells,targetingthemfordestructionintheproteosome(seeProteosomepathway).OneoftheproteinsthatparkinnormallytargetsfordestructionisaspecificO-glycosylatedformofalpha-synuclein.Failureofparkin-mediateddegradationofalpha-synucleinmaybeakeyfactorleADIngtothedeathofdopaminergicneurons.AnothersubstrateofparkinisaGPCR-likeproteincalledPael-RthataccumulatesintheERofaffectedcellsandmaycauseneuronalcelldeath.TheinvolvementofParkinandalpha-synucleinmutationsingeneticformsofParkinson"ssuggestthatfailureofubiquitinationandproteindegradationmaybecausativeinotherformsofParkinson"s.QuestionsremainingincludethecauseofthelackofeffectiveubiquitinationinindividualslackingobviousgeneticdefectsinthispathwayandhowtousethisknowledgeofubiquitinationandproteindegradationinParkinson"sdiseasetoidentifytherapeuticstrategies.

Contributor:GlennCrostonPh.D.

REFERENCES:Chung,KennyK.K.,etal.Parkinubiquitinatesthealpha-synuclein-intractingprotein,synphilin-1:implicationsforLewy-bodyformationinParkinsondisease.NatureMedicine,vol7(10)October2001,1144-50.Chung,,KennyK.K.,ValinaL.Dawson,andTedM.Dawson.TheRoleoftheUbiquitin-ProteasomalPathwayinParkinsonsDiseaseandOtherNeurodegenerativeDisorders.TINS,vol24,November2001,S7-S14.Ciechanover,Aaron.Linkingubiquitin,parkinandsynphilin-1.NatureMedicine,vol7(10),October2001,1108-09.Haass,ChristianandPhilippJ.Kahle.Parkinanditssubstrates.Science,vol293,July2001,224-25.ImaiY,etal.Anunfoldedputativetransmembranepolypeptide,whichcanleadtoendoplasmicreticulumstress,isasubstrateofParkin.Cell,vol105(7),Jun2001,891-902.Shimura,Hideki,etal.UbiquitinationofaNewFormofa-SynucleinbyParkinfromHumanBrain:ImplicationsforParkinsonsDisease.Science,vol293,July2001,63-269.

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