SnapShot:PathogenesisofParkinson’sDiseaseJoo-HoShin,ValinaL.Dawson,andTedM.DawsonNeuroRegenerationandStemCellPrograms,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD21205,USASeeonlineversionforlegendandreferences.440Cell139,October16,2009©2009ElsevierInc.DOI10.1016/j.cell.2009.09.026SnapShot:PathogenesisofParkinson’sDiseaseJoo-HoShin,ValinaL.Dawson,andTedM.DawsonNeuroRegenerationandStemCellPrograms,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD21205,USA440.e1Cell139,October16,2009©2009ElsevierInc.DOI10.1016/j.cell.2009.09.026Parkinson’sdisease(PD)isthemostcommonmovementdisordercharacterizedbydeathofdopaminergicneuronsinthesubstantianigraparscompacta.SophisticatedgeneticanalysishasrevealedseveralPD-associatedgenesincludingthoseencodingα-synuclein,parkin,PINK1,DJ-1,LRRK2,andATP13A2(seetable).DiverseenvironmentalfactorsinconjunctionwithgeneticriskfactorsleadtoPDpathogenesis,althoughtheexactmechanismsarestillunderinvestigation.ThisSnapShotsummarizestherolesthatproteinsencodedbyPD-associatedgenesplayinbothcommonanddivergentmechanismsofPDpathogenesis.DeathofDopaminergicNeuronsUnlikemostotherbrainneurons,thedopaminergicneuronsofthesubstantianigrauseL-typeCa2+channels(containingadistinctiveCav1.3pore-formingsubunit,Cacna1d)forpacemaking,resultinginincreasedATPconsumptionandCa2+influx.Ca2+enterstheendoplasmicreticulum(ER)viaahigh-affinitysmoothERCa2+(SERCA)pump.Ca2+flowsbackintothecytoplasmthroughinositoltrisphosphatereceptors(IP3R)andryanodinereceptors(RyR)formingahigh-concentrationCa2+zonenearmitochondria.Mitochondriaindopamin-ergicneuronstakeupCa2+viatheCa2+uniporter,whereasmitochondrialCa2+effluxismediatedbytheNa+/Ca2+exchanger(NCX).MitochondriaareakeytargetinPDandimpairedmitochondriacontributetodeathofdopaminergicneurons.DuetotheiruniqueCav1.3calciumchannels,dopaminergicneuronsaremorevulnerabletoenvironmentaltoxins,suchas1-methyl-4-phenyl-1,2,3,6tetrahydropyridine(MPTP).MPTPselectivelykillsdopaminergicneuronsbyblockingtheactivityofmitochondrialcomplexI...
