基底神经节疾病优质课件

基底神经节疾病基底神经节疾病基底神经节疾病Outline1.IntroductionofbasalgangliaOverviewandfunction,structure,andconnections2.DisordersofbasalgangliaParkinsonsdiseaseHuntingtonsdisease(symptomatology,pathology,pothogenesis,treatment)Outline1.Introductionofbasal1.IntroductionofbasalgangliaOverviewandfunctionStructureConnections1.IntroductionofbasalgangliThebasal gangliaareagroup of nuclei in the braininterconnectedwiththecerebralcortex,thalamusandbrainstem.Functions:motorcontrol,cognition,emotions,andlearning.Thebasalgangliaareagroup锥体系统锥体系统锥体系统internalglobuspallidus(GPi)externalglobuspallidus(GPe)internalglobuspallidus基底神经节疾病优质课件ConnectionsConnectionsCircuitofBasalGangliaDirectpathwayIndirectpathwayNigrostriatalpathwayCircuitofBasalGangliaDirectGlutamateGABADopamineGlutamateDirect:MotorcortexPutamenGPiThalamusMotorcortexIndirect:MotorcortexPutamenGPeSubthalamicnucleusGPiThalamusMotorcortexNigrostriatal pathway:ParscompactaStriatumGluGABAGABAGluGluGABAGABAGluGABAGluDirect:MotorcortexPutam2.DisordersofBasalGangliaDiminishedmovement:ParkinsonsdiseaseExcessivemovement:HuntingtondiseaseNeuropsychiatriccognitiveandbehavioraldisturbances2.DisordersofBasalGangliaParkinsons disease，PDAnEssayontheShakingPalsyEnglishphysicianJamesParkinson(1817)IntroductionPDisthemostcommonneurodegenerativedisorderafterAlzheimersdisease.Parkinsonsdisease，PDAnEssaTheprevalenceis0.3inthewholepopulationinindustrializedcountries,risingto1%inthoseover60yearsofageandto4%ofthepopulationover80.Meanageofonsetisaround60years,although5-10%ofcasesareconsideredofyoungonset(theageof20and50).Theincidenceisbetween8and18per100.000person-years.EpidemiologyTheprevalenceis0.3inthewMonograph by James Parkinson1817SymptomatologyMovementdisorders:restingtremormusclerigiditybradykinesiaandposturalinstabilityParkinsonismCognitiveandneurobehavioralproblems(dementia)SensoryandsleepdifficultieschronicandprogressiveMonographbyJamesParkinsonSyTherelationshipofthebasalgangliatothemajorcomponentsofthemotorsystem.TherelationshipofthebasalOriginsandterminationsof(a)thecorticospinaltractand(b)therubrospinaltract.Originsandterminationsof(a正常年青人，黑质细胞数为42.5万正常80岁老人，黑质细胞数减少到20.0万PD病人黑质细胞数减少到少于10.0万LewybodyPathology正常年青人，黑质细胞数为42.5万正常80岁老人，黑质细胞EtiologyEtiologyPathogenesisCircuit disorder of Basal GangliaGeneticDopamine oxidative stressToxinsOthersPathogenesisCircuitdisorderoCircuit disorder of Basal GangliainhibitionofthedirectpathwayexcitationoftheindirectpathwayCircuitdisorderofBasalGang基底神经节疾病优质课件多巴胺神经元为何会发生黑质部选择性的退行性变呢？多巴胺神经元为何会发生黑质部选择性的退行性变呢？氧化应激损伤氧化应激损伤1、外源性毒物的侵入2、神经黑色素的存在3、DA的氧化应激代谢4、清除自由基的能力不全多巴胺神经元为何会发生黑质部选择性的退行性变呢？氧化应激损伤图31-5多巴胺在神经元中的酶代谢及其代谢产物引自金国章,脑内多巴胺的生物医学1998年Fe2+Fe3+O2O2Fe2+Fe3+O2O2H2O2多巴胺半醌多巴胺半醌多巴胺醌多巴胺醌DAO2MAODOPACH2O2HVACOMTDopamine oxidative stress图31-5多巴胺在神经元中的酶代谢及其代谢产物Fe2+FeDopamine oxidative stressDopamineoxidativestressToxinsRotenone(aninsecticide)MPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（1-甲基-4-苯基-1,2,3,6-四氢吡啶）Paraquat(aherbicide)6-Hydroxydopamine(6-OHDA)HeavymetalsToxinsRotenone(aninsecticideRotenoneRotenoneMPTPMPTPParaquatParaquat6-Hydroxydopamine,or6-OHDA6-Hydroxydopamine,or6-OHDATheneurotoxinsusedinanimalmodelsofPDinducemitochondrialdysfunction.Theneurotoxinsusedinanimal一种理想的动物模型应该符合下列5种标准：1.出生时，应有正常而完整的DAneurons，并在成年期开始逐渐退化丧失且超过50%。2.具有容易检测的运动功能障碍。3.Lewybodies的形成。4.如模式是genetic，应以单一点突变为基础。5.较短的时程，约数月。一种理想的动物模型应该符合下列5种标准：1.出生时，应有基底神经节疾病优质课件Geneticmitochondrial dysfunction,oxidative damage,abnormal protein accumulation and protein phosphorylation Geneticmitochondrialdysfuncti1.Synuclein(SNCA)/PARK1seenmainlyinpresynapticterminalsinclude,and-synucleinplay a role in synaptic vesicle recycling,storageandcompartmentalizationofneurotransmittersandassociateswithvesicularandmembranousstructures1.Synuclein(SNCA)/PARK1seenmSer129的磷酸化-synuclein基因的倍增Ser129的磷酸化-synuclein基因的倍增Overviewofthea-synaggregationprocessintegratedwiththeoxidativestresspathwayandtheUPP.Overviewofthea-synaggregatParkinfunctionsasanE3ubiquitinproteinligasebytargetingmisfoldedproteinstotheubiquitnproteasomepathwayfordegradation,andthelossofitsE3ligaseactivityduetomutationsleadtoautosomalrecessiveearly-onsetPD.2.Parkin/PARK2ParkinfunctionsasanE3ubiqubiquitin proteasome system，UPS ubiquitinproteasomesystem，UP3.PINK1(PTEN-inducedputativekinase1)/PARK6serinethreoninekinase(mitochondria)apivotalregulatorofmitochondrialquality3.PINK1(PTEN-inducedputative4.UCH-L1/PARK5utativekinase1(PINK1)Ubiquitincarboxyl-terminalhydrolaseL1neuron-specificproteinPGP9.5oneofthemostabundantproteinsinthebrain(2%)hydrolytic activity,ligase activity and bindingmono-ub4.UCH-L1/PARK5utativekinase1PossibleroleofUCH-L1inPD.PossibleroleofUCH-L1inPD.基底神经节疾病优质课件基底神经节疾病优质课件Mechanismsofneurotoxicant-inducedproteasomedysfunctionanddopaminergicdegeneration.Mechanismsofneurotoxicant-inTransgenicanimalmodelalpha-synucleinA30P+A53T,LRRK2(R1441G),parkin,R621Csynphilin-1mouse,C.elegans,Drosophila,zebrafishTransgenicanimalmodelalpha-InflammationNeuroinflammationismediatedpredominatelybymicroglia,theresidentimmuno-competentandphagocyticcellswithintheCNS.Microglia,representing520%ofbraincellsMicroglialcelldensityintheSNis45timeshigherthaninotherregionsActivatedcellsalsoproducepro-inflammatorymoleculesInflammationNeuroinflammation基底神经节疾病优质课件Schematicrepresentationoflipopolysaccharide(LPS)-inducedandglialactivation-mediateddopamine(DA)neurodegeneration.SchematicrepresentationoflKeymolecularmechanismsthatarewidelyacceptedtocontributetotheneurodegenerative process in dopaminergic neurons in the substantianigrainParkinsondisease.KeymolecularmechanismsthatAtleasttwoofthethreemajorsymptomsarepresent.PossiblecausesforsymptomsResponsetolevodopaThemaintoolsusedtomakeadiagnosis:NeurologicalexaminationMotorphysiologytestsNeuro-imaging:PET(18-flurodopa),CT,MRILewybodiesduringautopsy(goldstandard)DiagnosisAtleasttwoofthethreemajo基底神经节疾病优质课件TreatmentThere is no known cure for Parkinsonsdisease.Treatmentisaimedatcontrollingthesymptoms.Medicationscontrolsymptoms primarily by controlling theimbalancebetweenthetransmitters.TreatmentThereisnoknownTherapeuticstrategyDirectlyimprovethefunctionofdopamineneurotransmissionIndirectlyimprovethefunctionofdopamineSurgeryanddeepbrainstimulationTherapeuticstrategyDirectlyidopamineinthebrain Precursor Rate-limiting step,decrease in PDL-dopadopamineinthebrainPrecursPeripheral inhibitorsThecentralandperipheralmetabolismoflevodopaanditsmodificationbydrugs.PeripheralinhibitorsThecentreasilypassthroughtheblood-brainbarrieristransformedintodopamineinthedopaminergicneuronsbyDDCisoftenmetabolisedtoDAelsewhere,causingawidevarietyofsideeffectsCOMTinhibitors,MAO-BinhibitorsL-dopaeasilypassthroughtheblood-Long-termeffectsofL-DOPA：On/offoscillationsDosefailure(drugresistance)DopaminedysregulationsyndromeLong-termeffectsofL-DOPA：Ach:movementAch increases inhibition o GABAdenosine:movementAdenosine increase the effects of Ach on the GABAergic neurons;Adenosine counter D2 receptor activity;Adenosine reduces GABA release.Ach:movementEnkephalin DynorphinPeptidemodulationofstriatalinputtotheglobuspollidus.EnkephalinPeptidemodulationPallidotomy and SubthalamotomyPallidotomyandSubthalamotomySurgeryisusedinpeoplewithadvancedPDfor whom drug therapy is no longersufficient.Becausetheseprocedurescausepermanentdestructionofbraintissue,theyhave largely been replaced by deep brainstimulation(DBS)fortreatmentofParkinsonsdisease.SurgeryisusedinpeoplewithDBSisprimarilyusedtostimulateoneofthreebrainregions:thesubthalamic nucleus,the globus pallidus,orthethalamus.DBSisprimarilyusedtostimuResearchdirectionsAnimal modelsGene therapy(virus)Neuroprotective treatments(GDNF)Neural transplantationStem cells transplants have raised great recent interest.Whentransplantedintothebrainsofrodentsandmonkeystheysurviveandimprovebehavioralabnormalities.Nevertheless while fetal stem cells are the easiest tomanipulatetheiruseiscontroversial.Suchcontroversymaybeovercomewiththeuseofinducedpluripotentstemcellsfromadults.ResearchdirectionsAnimalmodA scheme of the generation of induced pluripotent stem(iPS)cells.(1)Isolateandculturedonorcells.(2)Transfectstemcell-associatedgenesintothecellsbyviral vectors.Red cells indicate the cells expressing the exogenous genes.(3)Harvest and culture the cells according to ES cell culture,using mitoticallyinactivated feeder cells(lightgray).(4)A small subset of the transfected cellsbecomeiPScellsandgenerateES-likecolonies.Aschemeofthegenerationof主要讲解的内容主要讲解的内容:1基底神经节的脑内组成的核团、它们的分布、主要通路的组成 及其参与调节每条通路中的神经递质及其功能。2基底神经节（黑质）损伤后的主要临床表现及其病理表现的关系。3 PD脑内黑质多巴胺神经元退化的机制研究。4 Parkinsons Disease(PD)的治疗方案及治疗基础。主要讲解的内容:思考题：1Whatarethecomponentsofthebasalganglia?2Howarethestructuresofthebasalgangliaconnected?3Describethecorticostriatalprojections.4Describetheconnectionsbetweensubthalamusandglobuspallidus.5Describetheimportanceofthenigrastritalpathways.6Whatistheroleofthebasalgangliainrelationtothemotorthalamus?7Whataretheprincipalneurotransmittersandreceptorsassociatedwiththebasalganglia?8Adisorderofthebasalgangliaisindicatedwhatsigns?9CanadministrationofdopaminecureParkinsonsdisease?Why?10.DescribetheetiologyofneurodegenerationinthesubstantianigrainPD.11.WhydoselesioningtheSThnorGPreducethesymptomsofPD?思考题：Huntingtonsdisease(HD)In1872GeorgeHuntingtonthoroughlydescribedthedisorderinhisfirstpaperOnChorea.IntroductionTheworldwideprevalenceofHDis5-10casesper100,000persons.Itusuallyappearsinmiddleage(30-50years)EpidemiologyHuntingtonsdisease(HD)IntroHD/choreaisaninherited（autosomaldominantinheritance）progressiveneurodegenerativedisorder,whichaffectsmusclecoordinationandleadstocognitivedeclineanddementia.Ittypicallybecomesnoticeableinmiddleage.abnormalitiesinperipheraltissues(muscleatrophy,cardiacfailure,impairedglucosetolerance)SymptomatologyHD/choreaisaninherited（aProminentcelllossandatrophyinstriatum.astrocytesPathologynuclearandcytoplasmicinclusionsProminentcelllossandatrophPathogenesisPathogenesisPathogenesisPathogenesisHttisexpressedinallmammaliancells.(brain)interactswithover100otherproteins,andappearstohavemultiplebiologicalfunctions.embryonicdevelopment,anti-apoptosis,controlingtheproductionofBDNF,facilitatingvesiculartransportandsynaptictransmission,andcontrolingneuronalgenetranscription.Pathogenesis1.Loss of Htt function2.Toxic function of mHttHttisexpressedinallmammal基底神经节疾病优质课件GlutamateGABADopamineGlutamateDiagnosistypicalsymptomsafamilyhistoryofthediseasegenetictestingtohavetheexpandedtrinucleotiderepeatphysicalexamination,psychologicalexamination,MedicalimagingDiagnosistypicalsymptomsThereisnoknowncureforHD.Treatmentisaimedatcontrollingthesymptoms.tetrabenazine(chorea)antipsychoticdrugsTreatmentThereisnoknowncureforHD.PrognosisThe length of the trinucleotide repeataccounts for 60%of the variation in theageofonsetandtherateofprogressionofsymptoms.A longer repeat results in anearlierageofonsetandafasterprogressionofsymptoms.LifeexpectancyinHDisgenerallyaround20years following the onset of visiblesymptoms.PrognosisThelengthofthetrResearch directionsAppropriateanimalmodels(transgenicanimals)Geneticallyengineeredintrabodies(aninhibitionof mHtt aggregation)have been shown topreventmortalityduringthedevelopmentstagesofDrosophilamodels.Genesilencing(mHttisreduced)StemcelltherapyNumerousdrugsResearchdirectionsAppropriatThank you！Thankyou！