神经退行性疾病分子病理学研究进展

神经退行性疾病分子病理学研究进展Nov7th,2017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NatRevNeurosci2003,4:49-60ProteindepositioninthebrainofdifferenttypesofneurodegenerativediseasesCerebralaggregatesinneurodegenerativediseasesNatRevNeurosci2003,4:49-60Extracellularamyloidplaques(whitearrows)andintracytoplasmicneurofibrillarytangles(yellowarrows)arethepathologicalsignatureofAlzheimer’sdisease.IntracytoplasmicaggregatesaretypicallypresentintheneuronsofpeopleaffectedbyParkinson’sdiseaseandamyotrophiclateralsclerosis.IntranuclearinclusionsofhuntingtinareobservedinHuntington’sdiseasepatientsExtracellularprionamyloidplaquesthatarelocatedindifferentbrainregionsarepresentinsomecasesoftransmissiblespongiformencephalopathy.Inspiteofthedifferentproteincompositions,theultrastructureofthesedepositsseemstobesimilarandcomposedmainlyofanetworkoffibrillarpolymers(centre).神经退行性疾病：蛋白质异常聚集NatRevNeurosci2003,4:49-60AbnormalAccumulationofProteinsintheBrainIsDependentonTheirProductionandClearance

ColdSpringHarbPerspectMed2012,2(6):a006379AβDP:Aβ-degradingproteaseUPSAutophagySelkoeetal,2001AmyloidPrecursorProtein(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,2001AmyloidPrecursorProtein(APP)andItsProcessing基因突变或过表达可导致相关蛋白生成增加Selkoeetal,2001AmyloidPrecursorProtein(APP)andItsProcessingDownsyndrome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.Huntington’sdisease:

Huntingtinproteininheritedautosomaldominantdisordermotorimpairment,personalitychangespolyglutaminerepeatintheHuntingtinproteinofsomepeoplecausesselfassociationoftheproteininnervecellsintranuclearinclusionskillingnervecellsPolyglutamine(PolyQ)Repeat>36repeatsinHDHuntington’sdisease:

Huntingtinprotein舞蹈症Parkinson’sdisease:

alpha-synucleinLewybodies(路易小体)forminbraincellsKillcellsinpartofbrain(midbrain)thatproducesdopamineLessdopaminemeansmotorcontrollossLewyBodyAlpha-synucleinTheLewybodyisthepathologicalhallmarkofParkinsondisease.ClassicalLewybodiesareoftenfoundinthecytoplasmofaffectedpigmentedneuronsofthesubstantianigra.TheLewybodyinclusionshowsaneosinophiliccoresurroundedbyapalehalo(arrow).Theproteinalpha-synucleinisacomponentoftheLewybody.NeuronallossinParkinson’sdisease中脑切片LossofDopamineNeuronsinParkinson’sDiseaseLossofDopamineNeuronsinParkinson’sDiseaseParkinson’sdiseaseALS:amyotrophiclateralsclerosisAmytrophiclateralsclerosis.ALSisaprogressivefataldiseasecausedbydegenerationoflowermotorneuronsinthelateralhornofthespinalcordanduppermotorneuronsofthecerebralcortex,resultinginprogressivemotorweakness.Superoxidedismutase(SOD1)/TDP-43/C9ORF72ALS:amyotrophiclateralsclerosisSuperoxidedismutase1(SOD1)NatureReviewsNeuroscience2013，14,248-264

PrPcPrPscsoluble

+

-enzymedigesting

+

-polypeptidechainα-helicalsegmentß-sheetPrionproteinThenativestate(endogenouscellularprionprotein,PrPC)iswater-soluble,presentinginhealthycells,withpossiblefunctionintransmembranetransportorsignaling;Theotherconformationalstate(misfolded,disease-associatedPrPSc(Scmeaningscrapie-associated)isverypoorlywater-solubleandreadilyformsproteinaggregates.Prionproteinimmunoreactivity(purple)andspongiformdegenerationintheneocortexofapatientwhohaddiedofCreutzfeldt-Jakobdisease(CJD)动物prion病

人类prion病

羊瘙痒病(scrapieofsheepandgoat)

库鲁病(Kurudisease)

水貂传染性脑病(transmissibleminkencephalopathy,TMM)克-雅病(Creutzfeld-Jakobdisease,CJD)鹿慢性退行性变(chronicwastingdiseaseofdeer,CWD)格斯特曼综合征(Grestmann-StrausslerSyndrome,GSS)牛海绵状脑病(bovinespongiformencephalopathy,BSE)致死性家庭失眠症(fatalfamilialinsomnia,FFI)

猫海绵状脑病(felinespongiformencephalopathy,FSE)克-雅病变种(variantCJD,v-CJD)

Prion-associatedDiseasesinHumanandOtherAnimalsStanleyB.PrusinerDr.PrusineratUCSFcoinedthetermprion,whichcomesfrom"proteinaceousinfectiousparticlethatlacksnucleicacid"(缺乏核酸的蛋白质感染因子)torefertoapreviouslyundescribedformofinfectionduetoproteinmisfolding.Alzheimer’sdiseasePlaques(Amyloid:A42)NFT(Tau,p-Tau)Extracellularamyloidplaques;Intracellularneurofibrillarytangles(NFT)Neurology2012,79(16):1636-44FlorbetapirF18PETcanimageamyloid-β(Aβ)aggregatesinthebrainsoflivingsubjectsAβdepositsinmousemodelsofADStructuralChangesinBrainsofADPatients

FromInternet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TheGeneticsofAlzheimer'sDiseaseModifiedfromTanziandBertram,Cell,2005EtiologyofParkinson’sDiseaseGenetichypothesis

SNCA:encodingα-synuclein

PARK2:encodingtheE3ubiquitinligaseparkin

PARK6:encodingPINK1,amitochondrialkinase

PARK7:encodingtheproteinDJ-1

PARK8:encodingleucine-richrepeatkinase2(LRRK2)

PARK9:encodingATP13A2TheGeneticsofALSNatureReviewsNeuroscience

14,248-264(April2013)TheGeneticsofALSNatureReviewsNeuroscience

14,248-264(April2013)MPTP

(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine):aneurotoxinprecursortoMPP+,whichcausespermanentsymptomsofParkinson'sdiseasebydestroyingdopaminergicneuronsinthesubstantianigraofthebrain.

Rotenone:

pesticide鱼藤酮Paraquat:herbicide百草枯

Maneb:fungicide代森锰Environmentaltoxinhypothesis

(以PD为例)

ToxicityofMPTPinMiceNatureProtocols,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……ModelsfortheToxicMechanismof

MisfoldedAggregatesAtleastfourhypotheseshavebeenproposedtoexplainthemechanismofneurotoxicityassociatedwithproteinmisfoldingandaggregation:activationofanapoptoticsignallingpathwayrecruitmentofessentialcellularfactorsformationofionchannelstheinductionofoxidativestress.aggregatesNatRevNeurosci2003,4:49-60ModelsfortheMechanismofCellularToxicityassociatedwithProteinMisfoldingandAggregationNatRevNeurosci2003,4:49-60DiseasesSchematicRepresentationofMitochondrialCompartmentalizationImmuneContributionstoPDPathogenesis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SolubleoligomersaremoretoxicNatRevNeurosci2003,4:49-60Neurodegeneration:Amyloid-βpathologyinducedinhumansNature.

2015Sep10;525(7568):247-50Nature.2015Sep10;525(7568):193-4.Summaryofevidencesupportingthepropagationandtransmissionofnon-prionneurodegenerativediseaseproteinsNatureReviewsNeuroscience

16,109–120(2015)TheprionparadigmofseededproteinaggregationTauAcetylationandADNatureCommunicationsCriticalroleofacetylationintau-mediatedneurodegenerationandcognitivedeficits.NatMed.2015，21(10):1154-1162CircuitsorNetworkMechanismsofNeurodegenerativeDisordersAberrantNeuralNetworkActivityMayCauseCognitiveDysfunctioninADPalopJ,NatNeurosci2010Summary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FurtherReadingα-Synucleinstrainscausedistinctsynucleinopathiesafterlocalandsystemicadministration.Nature.2015Jun18;522(7556):340-4.η-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-βpathologyandcerebralamyloidangiopathy.Nature.2015Sep10;525(7568):247-50.PersistenceofAβseedsinAPPnullmousebrain.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.Pathologicalα-synucleintransmissioninitiatesParkinson-likeneurodegenerationinnontransgenicmice.Science338,949–953(2012).DeJesus-Hernandez,M.etal.ExpandedGGGGCChexanucleotiderepeatinnoncodingregionofC9ORF72causeschromosome9p-linkedFTDandALS.Neuron72,245–256(2011).Renton,A.E.etal.AhexanucleotiderepeatexpansioninC9ORF72isthecauseofchromosome9p21-linkedALS-FTD.Neuron72,257–268(2011).Spreadingofpathologyinneurodegenerativedisease:afocusonhumanstudies.

NatureReviewsNeuroscience16,109–120.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。Immuneattack:theroleofinflammationinneurodegenerativediseasesNatureReviewsNeuroscience

16,358–372(2015)TwoPathwaysto

Aggregation.Aβpeptidesformeithersmall,type1oligomers,whichstrayintosynapsesanddisruptmemory,orlarge,stableaggregates,whichclumpintoplaques.Plaquesthengiverisetolocal,fibril-liketype2oligomers.[ImagecourtesyofCellReports,Liuet

al.]Aggregatesofthephosphorylatedmicrotubule-associatedproteintauinneurofibrillarytanglesandneuropilthreads,togetherwithdepositsofamyloid-β(Aβ),arecharacteristicofsporadicAlzheimerdisease(AD).Taupathologyalonealsocharacterizesasubgroupofcasesoffrontotemporallobardegeneration(FTLD),whichisdesignatedasFTLD-tau,aswellasotherraretauopathies.Moreover,neuronalaccumulationsofα-synucleininLewybodiesandLewyneuritesarethepathologicalsignaturesofsporadicParkinsondisease(PD)andPDwithdementia,aswellasofdementiawithLewybodies.Furthermore,almostallcasesofamyotrophiclateralsclerosis(ALS)andafurthersubgroupofcasesofFTLD(FTLD-TDP)arecharacterizedbyaggregatesofTARDNA-bindingprotein43(TDP4