神经病理学研究进展

神经退行性疾病分子病理学研究进展,孙秉贵浙江大学神经科学研究所bsun,Oct.12th,2015,课程提纲,神经退行性疾病的病理变化神经退行性疾病的致病因素及其机制神经退行性疾病的研究进展,课程提纲,神经退行性疾病的病理变化神经退行性疾病的致病因素及其机制神经退行性疾病的研究进展,神经退行性疾病,神经退行性疾病（neurodegenerativediseases）是一类慢性、随着年龄增长而进行性加重的神经系统疾病，由神经退行性病变而引起。,Neurodegenerationisthetermfortheprogressivelossofstructureorfunctionofneurons,includingdeathofneurons.,常见神经退行性疾病,NatRevNeurosci2003,4:49-60,Proteindepositioninthebrainofdifferenttypesofneurodegenerativediseases,Cerebralaggregatesinneurodegenerativediseases,NatRevNeurosci2003,4:49-60,Extracellularamyloidplaques(whitearrows)andintracytoplasmicneurofibrillarytangles(yellowarrows)arethepathologicalsignatureofAlzheimersdisease.IntracytoplasmicaggregatesaretypicallypresentintheneuronsofpeopleaffectedbyParkinsonsdiseaseandamyotrophiclateralsclerosis.IntranuclearinclusionsofhuntingtinareobservedinHuntingtonsdiseasepatientsandextracellularprionamyloidplaquesthatarelocatedindifferentbrainregionsarepresentinsomecasesoftransmissiblespongiformencephalopathy.Inspiteofthedifferentproteincompositions,theultrastructureofthesedepositsseemstobesimilarandcomposedmainlyofanetworkoffibrillarpolymers(centre).,神经退行性疾病：蛋白质异常聚集,NatRevNeurosci2003,4:49-60,AbnormalAccumulationofProteinsintheBrainIsDependentonTheirProductionandClearance,ColdSpringHarbPerspectMed2012,2(6):a006379,ADP:A-degradingproteaseUPSAutophagy,Selkoeetal,2001,AmyloidPrecursorProtein(APP)andItsProcessing,基因突变或过表达可导致相关蛋白生成增加,基因突变或过表达可导致相关蛋白生成增加,Selkoeetal,2001,AmyloidPrecursorProtein(APP)andItsProcessing,蛋白质错误折叠与异常聚集,NatRevNeurosci2003,4:49-60,蛋白质折叠异常影响蛋白质的降解和清除,SolublemisfoldedmonomersanddimerscanberecognizedbyboththeUPSorCMA(chaperone-mediatedautophagy)-relatedchaperones,andsubsequentlydegradedbyeitherofthesetwopathways.InthecaseofCMA,cytosolicproteins(i.e.,a-synuclein)arerecognizedbyachaperone(i.e.,Hsc70),whichdeliversthetargetproteintothelysosomeviaareceptorproteinpresentinthelysosomalmembrane.However,onmorecomplexassembly(oligomerorfibrilformation)ofthetargetprotein,macroautophagyistheonlymechanismavailabletoclearthemoreinsolubleandhighlyorderedaggregates.,Ubiquitin-ProteasomeProteolysis,Ubiquitinisfirstactivatedbytheubiquitin-activatingenzymeE1(A),anubiquitin-carrierprotein,E2,andATP.Theproductofthisreactionisahigh-energyE2ubiquitinthiolesterintermediate(B).Proteinsubstratesarethenubiquitinatedbyeitherbindingofthesubstratetoaspecificubiquitin-proteinligase(E3),andthentheE2-boundactivatedubiquitinistransferreddirectlytotheE3-boundproteinsubstrate.Oralternatively,theactivatedubiquitincanbetransferredfromtheE2totheE3,priortoitsconjugationtotheE3-boundsubstrate(C).Followingconjugationofthefirstubiquitinmoleculetotheproteinsubstrate,additionalubiquitinmoleculescanbeaddedtotheinternallysineresiduesofubiquitintoformapolyubiquitinchainonthesubstrate(D).Theubiquitinatedsubstrateisthenrecognizedanddegradedbythe26Sproteasomecomplex,leadingtothereleaseofshortpeptides(E).Ubiquitinisrecycledviatheactivityofdeubiquitinatingenzymes.,Autophagy,Autophagyisthebasiccatabolicmechanismthatinvolvescelldegradationofunnecessaryordysfunctionalcellularcomponentsthroughthelysosomalmachinery,Huntingtonsdisease:Huntingtinproteininheritedautosomaldominantdisordermotorimpairment,personalitychangespolyglutaminerepeatintheHuntingtinproteinofsomepeoplecausesselfassociationoftheproteininnervecellsintranuclearinclusionskillingnervecells,Polyglutamine(PolyQ)Repeat,36repeatsinHD,Huntingtonsdisease:Huntingtinprotein,舞蹈症,Parkinsonsdisease:alpha-synucleinLewybodiesforminbraincellsKillcellsinpartofbrain(midbrain)thatproducesdopamineLessdopaminemeansmotorcontrolloss,LewyBody,Alpha-synuclein,TheLewybodyisthepathologicalhallmarkofParkinsondisease.ClassicalLewybodiesareoftenfoundinthecytoplasmofaffectedpigmentedneuronsofthesubstantianigra.TheLewybodyinclusionshowsaneosinophiliccoresurroundedbyapalehalo(arrow).Theproteinalpha-synucleinisacomponentoftheLewybody.,NeuronallossinParkinsonsdisease,中脑切片,ALS:amyotrophiclateralsclerosis,Amytrophiclateralsclerosis.ALSisaprogressivefataldiseasecausedbydegenerationoflowermotorneuronsinthelateralhornofthespinalcordanduppermotorneuronsofthecerebralcortex,resultinginprogressivemotorweakness.,Superoxidedismutase(SOD1)/TDP-43/C9ORF72,Superoxidedismutase1(SOD1),NatureReviewsNeuroscience2013，14,248-264,Prionprotein,Thenativestate(endogenouscellularprionprotein,PrPC)iswater-soluble,presentinginhealthycells,withpossiblefunctionintransmembranetransportorsignaling;Theotherconformationalstate(misfolded,disease-associatedPrPSc(Scmeaningscrapie-associated)isverypoorlywater-solubleandreadilyformsproteinaggregates.,Prionproteinimmunoreactivity(purple)andspongiformdegenerationintheneocortexofapatientwhohaddiedofCreutzfeldt-Jakobdisease(CJD),Prion-associatedDiseasesinHumanandOtherAnimals,Alzheimersdisease,Plaques(Amyloid:A42),NFT(Tau,p-Tau),Extracellularamyloidplaques;Intracellularneurofibrillarytangles(NFT),AdepositsinmousemodelsofAD,课程提纲,神经退行性疾病的病理变化神经退行性疾病的致病因素及其机制神经退行性疾病的研究进展,神经退行性疾病的致病因素及其机制,年龄基因突变或过表达环境毒素未知因素,TheGeneticsofAlzheimersDisease,ModifiedfromTanziandBertram,Cell,2005,KeyGenomicDiscoveriesinPD,TheGeneticsofALS,NatureReviewsNeuroscience14,248-264(April2013),TheGeneticsofALS,NatureReviewsNeuroscience14,248-264(April2013),Environmentaltoxinhypothesis(以PD为例)MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine):aneurotoxinprecursortoMPP+,whichcausespermanentsymptomsofParkinsonsdiseasebydestroyingdopaminergicneuronsinthesubstantianigraofthebrain.Rotenone:pesticide鱼藤酮Paraquat:herbicide百草枯Maneb:fungicide代森锰,ToxicityofMPTPinMice,NatureProtocols,2007,致病途径,蛋白质错误折叠和聚集线粒体功能异常氧化应激炎症反应,ModelsfortheToxicMechanismofMisfoldedAggregates,Atleastfourhypotheseshavebeenproposedtoexplainthemechanismofneurotoxicityassociatedwithproteinmisfoldingandaggregation:activationofanapoptoticsignallingpathwayrecruitmentofessentialcellularfactorsformationofionchannelstheinductionofoxidativestress.,aggregates,NatRevNeurosci2003,4:49-60,ModelsfortheMechanismofCellularToxicityassociatedwithProteinMisfoldingandAggregation,NatRevNeurosci2003,4:49-60,Diseases,MechanismsofactionsofvarioustoxinsinPD,TIPS,2009,30:475-483,SchematicRepresentationofMitochondrialCompartmentalization,ImmuneContributionstoPDPathogenesis,课程提纲,神经退行性疾病的病理变化神经退行性疾病的致病因素及其机制神经退行性疾病的研究进展,Solubleoligomersaremoretoxic,NatRevNeurosci2003,4:49-60,-SecretaseprocessingofAPPinhibitsneuronalactivityinthehippocampus.Nature.2015Aug31,AnewsiteforAPPprocessing,NatNeurosci.2015Sep9.doi:10.1038/nn.4117.,TransmissionofNeurodegenerativeDiseases:ACommonMechanismforPathogenesis？,NatNeurosci.2015Sep9.doi:10.1038/nn.4117.,Neurodegeneration:Amyloid-pathologyinducedinhumans,Nature.2015Sep10;525(7568):247-50,Nature.2015Sep10;525(7568):193-4.,Summaryofevidencesupportingthepropagationandtransmissionofnon-prionneurodegenerativediseaseproteins,NatureReviewsNeuroscience16,109120(2015),Theprionparadigmofseededproteinaggregation,Taupost-translationalmodifications,NatNeurosci.2015Aug;18(8):1183-9.,TauAcetylationandAD,NatureCommunications,Criticalroleofacetylationintau-mediatedneurodegenerationandcognitivedeficits.NatMed.2015，21(10):1154-1162,CircuitsorNetworkMechanismsofNeurodegenerativeDisorders,AberrantNeuralNetworkActivityMayCauseCognitiveDysfunctioninAD,PalopJ,NatNeurosci2010,Immuneattack:theroleofinflammationinneurodegenerativediseases,NatureReviewsNeuroscience16,358372(2015),Summary,相关蛋白的过度聚集可导致神经退行性疾病基因突变或环境因素可导致蛋白质错误折叠，从而引起蛋白质过度聚集蛋白质异常折叠及其聚集可导致神经元死亡或功能障碍线粒体功能异常、氧化应激、炎症反应等在神经退行性疾病中起重要作用,FurtherReading,-Synucleinstrainscausedistinctsynucleinopathiesafterlocalandsystemicadministration.Nature.2015Jun18;522(7556):340-4.-SecretaseprocessingofAPPinhibitsneuronalactivityinthehippocampus.Nature.2015Aug31ThechangingsceneofamyotrophiclateralsclerosisNatureReviewsNeuroscience14,248-264(April2013)Criticalroleofacetylationintau-mediatedneurodegenerationandcognitivedeficits.NatMed.2015Sep21Taupost-translationalmodificationsinwild-typeandhumanamyloidprecursorproteintransgenicmice.NatNeurosci.2015Aug;18(8):1183-9.Acetylationoftauinhibitsitsdegradationandcontributestotauopathy.Neuron.2010Sep23;67(6):953-66.Evidenceforhumantransmissionofamyloid-pathologyandcerebralamyloidangiopathy.Nature.2015Sep10;525(7568):247-50.PersistenceofAseedsinAPPnullmousebrain.NatNeurosci.2015Sep9;,GGGGCCrepeatexpansioninC9orf72compromisesnucleocytoplasmictransport.Nature.2015Sep3;525(7567):129-33.TheC9orf72repeatexpansiondisruptsnucleocytoplasmictransport.Nature.2015Sep3;525(7567):56-61.ModifiersofC9orf72dipeptiderepeattoxicityconnectnucleocytoplasmictransportdefectstoFTD/ALS.NatNeurosci.2015Aug26;18(9):1226-9.Luk,K.C.etal.Pathological-synucleintransmissioninitiatesParkinson-likeneurodegenerationinnontransgenicmice.Science338,949953(2012).DeJesus-Hernandez,M.etal.ExpandedGGGGCChexanucleotiderepeatinnoncodingregionofC9ORF72causeschromosome9p-linkedFTDandALS.Neuron72,245256(2011).Renton,A.E.etal.AhexanucleotiderepeatexpansioninC9ORF72isthecauseofchromosome9p21-linkedALS-FTD.Neuron72,257268(2011).Spreadingofpathologyinneurodegenerativedisease:afocusonhumanstudies.NatureReviewsNeuroscience16,109120.,FurtherReading,思考题,名词解释：神经退行性疾病简答题：以阿尔茨海默病为例，简述神经退行性疾病中相关蛋白异常聚集的原因。简述蛋白质异常聚集引起神经退行性病变的机理。,TwoPathwaystoAggregation.Apeptidesformeithersmall,type1oligomers,whichstrayintosynapsesanddisruptmemory,orlarge,stableaggregates,whichclumpintoplaques.Plaquesthengiverisetolocal,fibril-liketype2oligomers.ImagecourtesyofCellReports,Liuetal.,Aggregatesofthephosphorylatedmicrotubule-associatedproteintauinneurofibrillarytanglesandneuropilthreads,togetherwithdepositsofamyloid-(A),arecharacteristicofsporadicAlzheimerdisease(AD).Taupathologyalonealsocharacterizesasubgroupofcasesoffrontotemporallobardegeneration(FTLD),whichisdesignatedasFTLD-tau,aswellasotherraretauopathies.Moreover,neuronalaccumulationsof-synucleininLewybodiesandLewyneuritesarethepathologicalsignaturesofsporadicParkinsondisease(PD)andPDwithdementia,aswellasofdementiawithLewybodies.Furthermore,almostallcasesofamyotrophiclateralsclerosis(ALS)andafurthersubgroupofcasesofFTLD(FTLD-TDP)arecharacterizedbyaggregatesofTARDNA-bindingprotein43(TDP43).,Late-onsetADriskallelesbyGWAS,HoltzmanD,2011,TREM2,HowCJDistransmittedTheriskofCJDislow.Thediseasecantbetransmittedthroughcoughingorsneezing,touchingorsexualcontact.Thethreewaysitdevelopsare:Sporadically.MostpeoplewithclassicCJDdevelopthediseasefornoapparentreason.TermedspontaneousCJDorsporadicCJD,thistypeaccountsforthemajorityofcases.Byinheritance.IntheUnitedStates,about5to10percentofpeoplewithCJDhaveafamilyhistoryofthediseaseortestpositiveforageneticmutationassoci