Neurodegeneration

张灼华2010年11月9日Contents1.Generalinformationandconcepts2.ParkinsondiseaseNeurodegenerativeDiseasestheDiseaseswithoutCureCostofNeurodegenerativeDiseasesConditionCases/Year1Cost/Year2Alzheimer’s4100Parkinson’s1.515Stroke4301casesinmillions2costinbillionsofdollarsHippokratesofKosca.460BC–ca.370BCBriefHistoryofNeurosciences(1)“notonlyinvolvedwithbutalsotheseatofintelligence.”Plato428/427BC–348/347BC“brainwastheseatoftherationalpartofthesoul.”CamilloGolgi(7/7/1843–1/21/1926)“enabletoviewthepathsofnervecellsinthebrainforthefirsttime.”SantiagoRamónyCajal(5/1/1852–10/17/1934)“extensiveobservations,descriptions,andcategorizationsofneuronsthroughoutthebrain.Hehypothesizedthatthefunctionalunitofthebrainistheneuron.“BriefHistoryofNeurosciences(2)Neurodegenerationistheprogressivelossofstructureorfunctionofneurons,includingdeathofneurons.Itcanbefoundinmanydifferentlevelsofneuronalcircuitryrangingfrommoleculartosystemic.NeurodegenerationNeurodegenerationinCajal’sEyesAlzheimer'sdiseaseAmyotrophiclateralsclerosisFriedreich'sataxiaHuntington'sdiseaseLewybodydiseaseParkinson'sdiseaseSpinalmuscularatrophyCommonNeurodegenerativeDiseasesGeneralCharacteristicsofNeurodegenerativeDiseases1.Selectiveneuronalloss2.Progressivedevelopment3.Agingandsexdependent4.Stronggeneticbackground5.Unknownetiology6.NocureSelectiveNeuronalLossAgeOnsetofCommonNDDiseasesOnsetAlzheimer'sdiseaseAround60Amyotrophiclateralsclerosis40-60Friedreich'sataxia8-15Huntington'sdisease30-50Lewybodydisease50-85Parkinson'sdiseaseAround60SpinalmuscularatrophySeveralmonthsto30sTherearemoremalecasesthanfemalecasesinmostND!However,therearemorefemalecasesthanmalecasesofAlzheimer’sdisease.GeneticBackgroundofNDDiseasesFamilialCasesAlzheimer'sdisease5-10%(APP,PS1,PS2,APOE4etc)Amyotrophiclateralsclerosis10%(SOD1,FUSetc)Friedreich'sataxia100%(frataxin)Huntington'sdisease100%(huntingtin)Lewybodydisease5-10%(Tau,GBAetc)Parkinson'sdisease10-15%(a-Syn,Parkin,PINK1etc)Spinalmuscularatrophy100%(SMN)DiseasesPathologyAlzheimer'sdiseaseAmyloidplaques,tangles.AmyotrophiclateralsclerosisIntracellularaggregatesFriedreich'sataxiaCytoplasmicinclusionsHuntington'sdiseaseNuclearaggregatesLewybodydiseaseLewybodyParkinson'sdiseaseLewyBodySpinalmuscularatrophyNuclearinclusionsPathologicalHallmarksofCommonNDExamplesofNeuropathologyofNDRoleofTauanda-synucleininneurodegenerativediseases最常见的运动神经退行性疾病复杂性疾病，病因及机制不明我国发病率1.7%（大于65岁)每年至少增加10万新病例主要临床特征：静止性震颤，肌强直，运动迟缓，姿势步态异常常伴发抑郁症、情绪异常、失眠等其他症状患者生活质量差，晚期不能自理尚无可以治愈或长期有效的药物ClinicalFeaturesofParkinson’sDiseaseInvoluntarytremulousmotion,withlessenedmuscularpower,inpartsnotinactionandevenwhensupported;withapropensitytobendthetrunkforwards,andtopassfromawalkingtoarunningpace:thesensesandintellectbeinguninjured.Parkinson’sDisease颤振症：“颤振者，人病手足摇动，如抖擞之状，筋脉约束不住，而莫能任持，风之象也。”孙一奎《赤水玄珠》(1584)“非寒禁鼓栗,乃木火上盛,肾阴不充,下虚上实,实为痰火,虚则肾亏”。“诸风掉眩，皆属于肝。”“诸暴强直，皆属于风……，诸痉项强，皆属于湿。”《素问至真要大论》(475-221B.C.)中医里的帕金森病PathologicalCharacteristicsofParkinson’sDiseaseLewybody(LB)formationLossofdopaminergicneuronsinsubstantianigraparscompacta帕金森病的可能病因环境因素•年龄老化•男性性别•应急•创伤(脑外伤，中风)•环境毒素的接触(herbicides,pesticides,etc)•抽烟【注意，抽烟与喝咖啡是能减少而不是增加本病的发生】遗传背景•基因突变•基因多态•表观遗传异常GeneticBackgroundofParkinson’sDiseaseLocusModeofInheritanceChr.LocalizationGenePARK1PARK2PARK3PARK4PARK5PARK6PARK7PARK8PARK9PARK104q21-236q25.2-272p134q4p141p35-361p3612p11-q13.11p361p32ADARADADADARARARADa-SynucleinParkin?a-SynucleinUchL1*PINK1DJ-1LRRK2ATP13A2?UnclearSusceptibilitygenes:NR4A2,synphilin-1,tau，bst1.PARK11PARK12PARK13PARK14PARK152q34-q37UnclearGIGYF2*XqX-linked?2p12UnclearHTRA2*22q12-q13ARFBXO722q12-q13UnclearPLA2G6PARK161q32Unclear?帕金森病相关基因的功能线粒体功能相关：PINK1,Parkin,DJ-1,HtrA2蛋白酶体功能相关：Parkin,PINK1,DJ-1,FBXO7,UchL1蛋白折叠相关：a-Synuclein,DJ-1,ATP13A2,LRRK2研究假设1:线粒体功能破坏和氧化应激Aggregationofa-synucleinDJ-1,ParkinPINK1,LRRK2HTRA2氧化应激神经毒性神经变性DopamineOxidation线粒体功能破坏MPP+pesticides线粒体假说依据MPP+,Paraquat,Rotenone作用于线粒体野生型ParkinNullGreeneetal,PNAS,2003.Parkin失活导致线粒体结构异常1.ParkJetal,MitochondrialdysfunctioninDrosophilaPINK1mutantsiscomplementedbyparkin.Nature,2006.2.ClarkIEetal,Drosophilapink1isrequiredformitochondrialfunctionandinteractsgeneticallywithparkin.Nature,2006.3.YangYetal,MitochondrialpathologyandmuscleanddopaminergicneurondegenerationcausedbyinactivationofDrosophilaPink1isrescuedbyParkin.ProcNatlAcadSciUSA.2006.4.WangDetal,AntioxidantsprotectPINK1-dependentdopaminergicneuronsinDrosophila.ProcNatlAcadSciUSA.2006.PINK1和线粒体CLacZhSODKDKD/lacZKD/hSODSOD1抑制dPINK1失活引起的复眼变性Wangetal,PNAS,2006.c100u1000uc20µg200µgSOD1维生素E抗氧化剂抑制dPINK1失活引起的复眼变性Wangetal,PNAS,2006.研究假说2：蛋白折叠和蛋白酶体功能异常新合成蛋白正确折叠蛋白异常折叠蛋白E1E2E3ParkinUchL1PINK1?DJ-1?a-Synuclein神经毒性神经保护神经变性和死亡分子伴侣分子伴侣泛素介导的蛋白酶体系统UbE1E1E2E2E3E3UbATPAMP+PPiUbSubstrateUbUbUbUbUbUbSubstrateUbUbUbUbUbUbUbE2UbE3E21.ShimuraHetal,FamilialParkinsondiseasegeneproduct,parkin,isaubiquitin-proteinligase.NatGenet.2000.2.ImaiYetal,Parkinsuppressesunfoldedproteinstress-inducedcelldeaththroughitsE3ubiquitin-proteinligaseactivity.JBiolChem.2000.3.ZhangYetal,ParkinfunctionsasanE2-dependentubiquitin-proteinligaseandpromotesthedegr