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.

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