基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件

基底神經(jīng)節(jié)疾病基底神經(jīng)節(jié)疾病Outline1.IntroductionofbasalgangliaOverviewandfunction,structure,andconnections2.DisordersofbasalgangliaParkinson’sdiseaseHuntington’sdisease(symptomatology,pathology,pothogenesis,treatment…)Outline1.Introductionofbasal1.IntroductionofbasalgangliaOverviewandfunctionStructureConnections

1.IntroductionofbasalgangliThe

basalganglia

areagroupofnucleiinthebraininterconnectedwiththecerebralcortex,thalamusandbrainstem.

Functions:

motorcontrol,cognition,emotions,andlearning.Thebasalgangliaareagroup錐體系統(tǒng)錐體系統(tǒng)internalglobuspallidus(GPi)externalglobuspallidus(GPe)

internalglobuspallidus基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件ConnectionsConnectionsCircuitofBasalGangliaDirectpathwayIndirectpathwayNigrostriatalpathwayCircuitofBasalGangliaDirectGlutamateGABA

Dopamine

GlutamateDirect:

Motorcortex→Putamen→GPi→Thalamus→Motorcortex

Indirect:

Motorcortex→Putamen→GPe→Subthalamicnucleus→GPi→Thalamus→MotorcortexNigrostriatalpathway:

Parscompacta→StriatumGluGABAGABAGluGluGABAGABAGluGABAGluDirect:Motorcortex→Putam2.DisordersofBasalGangliaDiminishedmovement:Parkinson’sdiseaseExcessivemovement:HuntingtondiseaseNeuropsychiatriccognitiveandbehavioraldisturbances2.DisordersofBasalGangliaParkinson’sdisease，PD"AnEssayontheShakingPalsy"EnglishphysicianJamesParkinson(1817)IntroductionPDisthemostcommonneurodegenerativedisorderafterAlzheimer'sdisease.Parkinson’sdisease，PD"AnEssaTheprevalenceis0.3inthewholepopulationinindustrializedcountries,risingto1%inthoseover60yearsofageandto4%ofthepopulationover80.Meanageofonsetisaround60years,although5-10%ofcasesareconsideredofyoungonset(theageof20and50).Theincidenceisbetween8and18per100.000person-years.EpidemiologyTheprevalenceis0.3inthewMonographbyJamesParkinson1817SymptomatologyMovementdisorders:restingtremormusclerigiditybradykinesiaandposturalinstability

ParkinsonismCognitiveandneurobehavioralproblems(dementia)Sensoryandsleepdifficulties

chronicandprogressiveMonographbyJamesParkinsonSyTherelationshipofthebasalgangliatothemajorcomponentsofthemotorsystem.

TherelationshipofthebasalOriginsandterminationsof(a)thecorticospinaltractand(b)therubrospinaltract.Originsandterminationsof(a正常年青人，黑質(zhì)細(xì)胞數(shù)為42.5萬(wàn)

正常80歲老人，黑質(zhì)細(xì)胞數(shù)減少到20.0萬(wàn)

PD病人黑質(zhì)細(xì)胞數(shù)減少到少于10.0萬(wàn)

LewybodyPathology正常年青人，黑質(zhì)細(xì)胞數(shù)為42.5萬(wàn)

正常80歲老人，黑質(zhì)細(xì)胞Etiology

Etiology

PathogenesisCircuitdisorderofBasalGangliaGeneticDopamineoxidativestressToxinsOthersPathogenesisCircuitdisorderoCircuitdisorderofBasalGangliainhibitionofthedirectpathwayexcitationoftheindirectpathwayCircuitdisorderofBasalGang基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件多巴胺神經(jīng)元為何會(huì)發(fā)生黑質(zhì)部選擇性的退行性變呢？氧化應(yīng)激損傷1、外源性毒物的侵入2、神經(jīng)黑色素的存在3、DA的氧化應(yīng)激代謝4、清除自由基的能力不全多巴胺神經(jīng)元為何會(huì)發(fā)生黑質(zhì)部選擇性的退行性變呢？氧化應(yīng)激損傷圖31-5多巴胺在神經(jīng)元中的酶代謝及其代謝產(chǎn)物引自金國(guó)章,腦內(nèi)多巴胺的生物醫(yī)學(xué)1998年Fe2+Fe3+O2O2·ˉFe2+Fe3+O2O2·ˉH2O2多巴胺半醌多巴胺醌DAO2MAODOPACH2O2HVACOMTDopamineoxidativestress圖31-5多巴胺在神經(jīng)元中的酶代謝及其代謝產(chǎn)物Fe2+FeDopamineoxidativestressDopamineoxidativestressToxinsRotenone(aninsecticide)MPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（1-甲基-4-苯基-1,2,3,6-四氫吡啶）Paraquat(aherbicide)6-Hydroxydopamine(6-OHDA)

HeavymetalsToxinsRotenone(aninsecticideRotenoneRotenoneMPTPMPTPParaquatParaquat6-Hydroxydopamine,or6-OHDA

6-Hydroxydopamine,or6-OHDATheneurotoxinsusedinanimalmodelsofPDinducemitochondrialdysfunction.Theneurotoxinsusedinanimal一種理想的動(dòng)物模型應(yīng)該符合下列5種標(biāo)準(zhǔn)：

1.出生時(shí)，應(yīng)有正常而完整的DAneurons，并在成年期開(kāi)始逐漸退化喪失且超過(guò)50%。

2.具有容易檢測(cè)的運(yùn)動(dòng)功能障礙。

3.Lewybodies的形成。

4.如模式是genetic，應(yīng)以單一點(diǎn)突變?yōu)榛A(chǔ)。

5.較短的時(shí)程，約數(shù)月。一種理想的動(dòng)物模型應(yīng)該符合下列5種標(biāo)準(zhǔn)：

1.出生時(shí)，應(yīng)有基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件Geneticmitochondrialdysfunction,oxidativedamage,abnormalproteinaccumulationandproteinphosphorylation

Geneticmitochondrialdysfuncti1.Synuclein(SNCA)/PARK1seenmainlyinpresynapticterminalsincludeα,βandγ-synucleinplayaroleinsynapticvesiclerecycling,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/PARK2ParkinfunctionsasanE3ubiqubiquitinproteasomesystem，UPS

ubiquitinproteasomesystem，UP3.PINK1(PTEN-inducedputativekinase1)/PARK6serine–threoninekinase(mitochondria)apivotalregulatorofmitochondrialquality3.PINK1(PTEN-inducedputative4.UCH-L1/PARK5utativekinase1(PINK1)Ubiquitincarboxyl-terminalhydrolaseL1neuron-specificproteinPGP9.5oneofthemostabundantproteinsinthebrain(2%)hydrolyticactivity,ligaseactivityandbindingmono-ub4.UCH-L1/PARK5utativekinase1PossibleroleofUCH-L1inPD.PossibleroleofUCH-L1inPD.基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件Mechanismsofneurotoxicant-inducedproteasomedysfunctionanddopaminergicdegeneration.Mechanismsofneurotoxicant-inTransgenicanimalmodelalpha-synucleinA30P+A53T,LRRK2(R1441G),parkin,R621Csynphilin-1…mouse,C.elegans,Drosophila,zebrafish

Transgenicanimalmodelalpha-Inflammation

Neuroinflammationismediatedpredominatelybymicroglia,theresidentimmuno-competentandphagocyticcellswithintheCNS.Microglia,representing5?20%ofbraincellsMicroglialcelldensityintheSNis4?5timeshigherthaninotherregionsActivatedcellsalsoproducepro-inflammatorymoleculesInflammation

Neuroinflammation基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件Schematicrepresentationoflipopolysaccharide(LPS)-inducedandglialactivation-mediateddopamine(DA)neurodegeneration.SchematicrepresentationoflKeymolecularmechanismsthatarewidelyacceptedtocontributetotheneurodegenerativeprocessindopaminergicneuronsinthesubstantianigrainParkinsondisease.KeymolecularmechanismsthatAtleasttwoofthethreemajorsymptomsarepresent.PossiblecausesforsymptomsResponsetolevodopaThemaintoolsusedtomakeadiagnosis:NeurologicalexaminationMotorphysiologytestsNeuro-imaging:PET(18-flurodopa),CT,MRI

Lewybodiesduringautopsy(goldstandard)

DiagnosisAtleasttwoofthethreemajo基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件Treatment

ThereisnoknowncureforParkinson'sdisease.Treatmentisaimedatcontrollingthesymptoms.Medicationscontrolsymptomsprimarilybycontrollingtheimbalancebetweenthetransmitters.TreatmentThereisnoknownTherapeuticstrategyDirectlyimprovethefunctionofdopamineneurotransmissionIndirectlyimprovethefunctionofdopamineSurgeryanddeepbrainstimulationTherapeuticstrategyDirectlyidopamine↑inthebrain

PrecursorRate-limitingstep,decreaseinPDL-dopadopamine↑inthebrainPrecursPeripheralinhibitorsThecentralandperipheralmetabolismoflevodopaanditsmodificationbydrugs.PeripheralinhibitorsThecentreasilypassthroughtheblood-brainbarrieristransformedintodopamineinthedopaminergicneuronsbyDDCisoftenmetabolisedtoDAelsewhere,causingawidevarietyofsideeffectsCOMTinhibitors,MAO-BinhibitorsL-dopaeasilypassthroughtheblood-Long-termeffectsofL-DOPA：

On/offoscillationsDosefailure(drugresistance)DopaminedysregulationsyndromeLong-termeffectsofL-DOPA：Ach:

movementAchincreasesinhibitionoｆ

GABＡ．Adenosine:movementAdenosineincreasetheeffectsofAchontheGABAergicneurons;AdenosinecounterD2receptoractivity;AdenosinereducesGABArelease.Ach:movementEnkephalinDynorphinPeptidemodulationofstriatalinputtotheglobuspollidus.EnkephalinPeptidemodulationPallidotomyandSubthalamotomy

PallidotomyandSubthalamotomySurgeryisusedinpeoplewithadvancedPDforwhomdrugtherapyisnolongersufficient.Becausetheseprocedurescausepermanentdestructionofbraintissue,theyhavelargelybeenreplacedbydeepbrainstimulation(DBS)fortreatmentofParkinson'sdisease.SurgeryisusedinpeoplewithDBSisprimarilyusedtostimulateoneofthreebrainregions:thesubthalamicnucleus,theglobuspallidus,orthethalamus.DBSisprimarilyusedtostimuResearchdirections

Animalmodels

Genetherapy(virus)Neuroprotectivetreatments

(GDNF)Neuraltransplantation

Stemcellstransplantshaveraisedgreatrecentinterest.Whentransplantedintothebrainsofrodentsandmonkeystheysurviveandimprovebehavioralabnormalities.Neverthelesswhilefetalstemcellsaretheeasiesttomanipulatetheiruseiscontroversial.Suchcontroversymaybeovercomewiththeuseofinducedpluripotentstemcellsfromadults.

ResearchdirectionsAnimalmodAschemeofthegenerationofinducedpluripotentstem(iPS)cells.

(1)Isolateandculturedonorcells.(2)Transfectstemcell-associatedgenesintothecellsbyviralvectors.Redcellsindicatethecellsexpressingtheexogenousgenes.(3)HarvestandculturethecellsaccordingtoEScellculture,usingmitoticallyinactivatedfeedercells(lightgray).(4)AsmallsubsetofthetransfectedcellsbecomeiPScellsandgenerateES-likecolonies.

Aschemeofthegenerationof主要講解的內(nèi)容:1．

基底神經(jīng)節(jié)的腦內(nèi)組成的核團(tuán)、它們的分布、主要通路的組成及其參與調(diào)節(jié)每條通路中的神經(jīng)遞質(zhì)及其功能。2．

基底神經(jīng)節(jié)（黑質(zhì)）損傷后的主要臨床表現(xiàn)及其病理表現(xiàn)的關(guān)系。3．PD腦內(nèi)黑質(zhì)多巴胺神經(jīng)元退化的機(jī)制研究。4．Parkinson’sDisease(PD)的治療方案及治療基礎(chǔ)。主要講解的內(nèi)容:思考題：1．Whatarethecomponentsofthebasalganglia?2．Howarethestructuresofthebasalgangliaconnected?3．Describethecorticostriatalprojections.4．Describetheconnectionsbetweensubthalamusandglobuspallidus.5．Describetheimportanceofthenigrastritalpathways.6．Whatistheroleofthebasalgangliainrelationtothemotorthalamus?7．Whataretheprincipalneurotransmittersandreceptorsassociatedwiththebasalganglia?8．Adisorderofthebasalgangliaisindicatedwhatsigns?9．CanadministrationofdopaminecureParkinson’sdisease?Why?10.DescribetheetiologyofneurodegenerationinthesubstantianigrainPD.11.WhydoselesioningtheSThnorGPreducethesymptomsofPD?

思考題：Huntington'sdisease(HD)In1872GeorgeHuntingtonthoroughlydescribedthedisorderinhisfirstpaper"OnChorea".IntroductionTheworldwideprevalenceofHDis5-10casesper100,000persons.

Itusuallyappearsinmiddleage(30-50years)EpidemiologyHuntington'sdisease(HD)IntroHD/chorea

isaninherited（autosomaldominantinheritance）progressiveneurodegenerativedisorder,whichaffectsmusclecoordinationandleadstocognitivedeclineanddementia.Ittypicallybecomesnoticeableinmiddleage.abnormalitiesinperipheraltissues(muscleatrophy,cardiacfailure,impairedglucosetolerance…)SymptomatologyHD/choreaisaninherited（aProminentcelllossandatrophyinstriatum.astrocytes↑PathologynuclearandcytoplasmicinclusionsProminentcelllossandatrophPathogenesisPathogenesisPathogenesisPathogenesisHttisexpressedinallmammaliancells.(brain)interactswithover100otherproteins,andappearstohavemultiplebiologicalfunctions.embryonicdevelopment,anti-apoptosis,controlingtheproductionofBDNF,facilitatingvesiculartransportandsynaptictransmission,andcontrolingneuronalgenetranscription.Pathogenesis1.LossofHttfunction

2.ToxicfunctionofmHttHttisexpressedinallmammal基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件GlutamateGABA

Dopamine

GlutamateDiagnosis

typicalsymptomsafamilyhistoryofthediseasegenetictestingtohavetheexpandedtrinucleotiderepeatphysicalexamination,psychologicalexamination,Medicalimaging

DiagnosistypicalsymptomsThereisnoknowncureforHD.Treatmentisaimedatcontrollingthesymptoms.tetrabenazine(chorea)antipsychoticdrugs

TreatmentThereisnoknowncureforHD.Prognosis

Thelengthofthetrinucleotiderepeataccountsfor60%ofthevariationintheageofonsetandtherateofprogressionofsymptoms.Alongerrepeatresultsinanearlierageofonsetandafasterprogressionofsymptoms.

LifeexpectancyinHDisgenerallyaround20

yearsfollowingtheonsetofvisiblesymptoms.PrognosisThelengthofthetrResearchdirections

Appropriateanimalmodels(transgenicanimals)Geneticallyengineeredintrabodies(aninhibitionofmHttaggregation)havebeenshowntopreventmortalityduringthedevelopment

stagesofDrosophilamodels.Genesilencing(mHttisreduced)StemcelltherapyNumerousdrugsResearchdirectionsAppropriatThankyou！Thankyou！基底神經(jīng)節(jié)疾病基底神經(jīng)節(jié)疾病Outline1.IntroductionofbasalgangliaOverviewandfunction,structure,andconnections2.DisordersofbasalgangliaParkinson’sdiseaseHuntington’sdisease(symptomatology,pathology,pothogenesis,treatment…)Outline1.Introductionofbasal1.IntroductionofbasalgangliaOverviewandfunctionStructureConnections

1.IntroductionofbasalgangliThe

basalganglia

areagroupofnucleiinthebraininterconnectedwiththecerebralcortex,thalamusandbrainstem.

Functions:

motorcontrol,cognition,emotions,andlearning.Thebasalgangliaareagroup錐體系統(tǒng)錐體系統(tǒng)internalglobuspallidus(GPi)externalglobuspallidus(GPe)

internalglobuspallidus基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件ConnectionsConnectionsCircuitofBasalGangliaDirectpathwayIndirectpathwayNigrostriatalpathwayCircuitofBasalGangliaDirectGlutamateGABA

Dopamine

GlutamateDirect:

Motorcortex→Putamen→GPi→Thalamus→Motorcortex

Indirect:

Motorcortex→Putamen→GPe→Subthalamicnucleus→GPi→Thalamus→MotorcortexNigrostriatalpathway:

Parscompacta→StriatumGluGABAGABAGluGluGABAGABAGluGABAGluDirect:Motorcortex→Putam2.DisordersofBasalGangliaDiminishedmovement:Parkinson’sdiseaseExcessivemovement:HuntingtondiseaseNeuropsychiatriccognitiveandbehavioraldisturbances2.DisordersofBasalGangliaParkinson’sdisease，PD"AnEssayontheShakingPalsy"EnglishphysicianJamesParkinson(1817)IntroductionPDisthemostcommonneurodegenerativedisorderafterAlzheimer'sdisease.Parkinson’sdisease，PD"AnEssaTheprevalenceis0.3inthewholepopulationinindustrializedcountries,risingto1%inthoseover60yearsofageandto4%ofthepopulationover80.Meanageofonsetisaround60years,although5-10%ofcasesareconsideredofyoungonset(theageof20and50).Theincidenceisbetween8and18per100.000person-years.EpidemiologyTheprevalenceis0.3inthewMonographbyJamesParkinson1817SymptomatologyMovementdisorders:restingtremormusclerigiditybradykinesiaandposturalinstability

ParkinsonismCognitiveandneurobehavioralproblems(dementia)Sensoryandsleepdifficulties

chronicandprogressiveMonographbyJamesParkinsonSyTherelationshipofthebasalgangliatothemajorcomponentsofthemotorsystem.

TherelationshipofthebasalOriginsandterminationsof(a)thecorticospinaltractand(b)therubrospinaltract.Originsandterminationsof(a正常年青人，黑質(zhì)細(xì)胞數(shù)為42.5萬(wàn)

正常80歲老人，黑質(zhì)細(xì)胞數(shù)減少到20.0萬(wàn)

PD病人黑質(zhì)細(xì)胞數(shù)減少到少于10.0萬(wàn)

LewybodyPathology正常年青人，黑質(zhì)細(xì)胞數(shù)為42.5萬(wàn)

正常80歲老人，黑質(zhì)細(xì)胞Etiology

Etiology

PathogenesisCircuitdisorderofBasalGangliaGeneticDopamineoxidativestressToxinsOthersPathogenesisCircuitdisorderoCircuitdisorderofBasalGangliainhibitionofthedirectpathwayexcitationoftheindirectpathwayCircuitdisorderofBasalGang基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件多巴胺神經(jīng)元為何會(huì)發(fā)生黑質(zhì)部選擇性的退行性變呢？氧化應(yīng)激損傷1、外源性毒物的侵入2、神經(jīng)黑色素的存在3、DA的氧化應(yīng)激代謝4、清除自由基的能力不全多巴胺神經(jīng)元為何會(huì)發(fā)生黑質(zhì)部選擇性的退行性變呢？氧化應(yīng)激損傷圖31-5多巴胺在神經(jīng)元中的酶代謝及其代謝產(chǎn)物引自金國(guó)章,腦內(nèi)多巴胺的生物醫(yī)學(xué)1998年Fe2+Fe3+O2O2·ˉFe2+Fe3+O2O2·ˉH2O2多巴胺半醌多巴胺醌DAO2MAODOPACH2O2HVACOMTDopamineoxidativestress圖31-5多巴胺在神經(jīng)元中的酶代謝及其代謝產(chǎn)物Fe2+FeDopamineoxidativestressDopamineoxidativestressToxinsRotenone(aninsecticide)MPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（1-甲基-4-苯基-1,2,3,6-四氫吡啶）Paraquat(aherbicide)6-Hydroxydopamine(6-OHDA)

HeavymetalsToxinsRotenone(aninsecticideRotenoneRotenoneMPTPMPTPParaquatParaquat6-Hydroxydopamine,or6-OHDA

6-Hydroxydopamine,or6-OHDATheneurotoxinsusedinanimalmodelsofPDinducemitochondrialdysfunction.Theneurotoxinsusedinanimal一種理想的動(dòng)物模型應(yīng)該符合下列5種標(biāo)準(zhǔn)：

1.出生時(shí)，應(yīng)有正常而完整的DAneurons，并在成年期開(kāi)始逐漸退化喪失且超過(guò)50%。

2.具有容易檢測(cè)的運(yùn)動(dòng)功能障礙。

3.Lewybodies的形成。

4.如模式是genetic，應(yīng)以單一點(diǎn)突變?yōu)榛A(chǔ)。

5.較短的時(shí)程，約數(shù)月。一種理想的動(dòng)物模型應(yīng)該符合下列5種標(biāo)準(zhǔn)：

1.出生時(shí)，應(yīng)有基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件Geneticmitochondrialdysfunction,oxidativedamage,abnormalproteinaccumulationandproteinphosphorylation

Geneticmitochondrialdysfuncti1.Synuclein(SNCA)/PARK1seenmainlyinpresynapticterminalsincludeα,βandγ-synucleinplayaroleinsynapticvesiclerecycling,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/PARK2ParkinfunctionsasanE3ubiqubiquitinproteasomesystem，UPS

ubiquitinproteasomesystem，UP3.PINK1(PTEN-inducedputativekinase1)/PARK6serine–threoninekinase(mitochondria)apivotalregulatorofmitochondrialquality3.PINK1(PTEN-inducedputative4.UCH-L1/PARK5utativekinase1(PINK1)Ubiquitincarboxyl-terminalhydrolaseL1neuron-specificproteinPGP9.5oneofthemostabundantproteinsinthebrain(2%)hydrolyticactivity,ligaseactivityandbindingmono-ub4.UCH-L1/PARK5utativekinase1PossibleroleofUCH-L1inPD.PossibleroleofUCH-L1inPD.基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件Mechanismsofneurotoxicant-inducedproteasomedysfunctionanddopaminergicdegeneration.Mechanismsofneurotoxicant-inTransgenicanimalmodelalpha-synucleinA30P+A53T,LRRK2(R1441G),parkin,R621Csynphilin-1…mouse,C.elegans,Drosophila,zebrafish

Transgenicanimalmodelalpha-Inflammation

Neuroinflammationismediatedpredominatelybymicroglia,theresidentimmuno-competentandphagocyticcellswithintheCNS.Microglia,representing5?20%ofbraincellsMicroglialcelldensityintheSNis4?5timeshigherthaninotherregionsActivatedcellsalsoproducepro-inflammatorymoleculesInflammation

Neuroinflammation基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件Schematicrepresentationoflipopolysaccharide(LPS)-inducedandglialactivation-mediateddopamine(DA)neurodegeneration.SchematicrepresentationoflKeymolecularmechanismsthatarewidelyacceptedtocontributetotheneurodegenerativeprocessindopaminergicneuronsinthesubstantianigrainParkinsondisease.KeymolecularmechanismsthatAtleasttwoofthethreemajorsymptomsarepresent.PossiblecausesforsymptomsResponsetolevodopaThemaintoolsusedtomakeadiagnosis:NeurologicalexaminationMotorphysiologytestsNeuro-imaging:PET(18-flurodopa),CT,MRI

Lewybodiesduringautopsy(goldstandard)

DiagnosisAtleasttwoofthethreemajo基底神經(jīng)節(jié)疾病優(yōu)質(zhì)課件Treatment

ThereisnoknowncureforParkinson'sdisease.Treatmentisaimedatcontrollingthesymptoms.Medicationscontrolsymptomsprimarilybycontrollingtheimbalancebetweenthetransmitters.TreatmentThereisnoknownTherapeuticstrategyDirectlyimprovethefunctionofdopamineneurotransmissionIndirectlyimprovethefunctionofdopamineSurgeryanddeepbrainstimulationTherapeuticstrategyDirectlyidopamine↑inthebrain

PrecursorRate-limitingstep,decreaseinPDL-dopadopamine↑inthebrainPrecursPeripheralinhibitorsThecentralandperipheralmetabolismoflevodopaanditsmodificationbydrugs.PeripheralinhibitorsThecentreasilypassthroughtheblood-brainbarrieristransformedintodopamineinthedopaminergicneuronsbyDDCisoftenmetabolisedtoDAelsewhere,causingawidevarietyofsideeffectsCOMTinhibitors,MAO-BinhibitorsL-dopaeasilypassthroughtheblood-Long-termeffectsofL-DOPA：

On/offoscillationsDosefailure(drugresistance)DopaminedysregulationsyndromeLong-termeffectsofL-DOPA：Ach:

movementAchincreasesinhibitionoｆ

GABＡ．Adenosine:movementAdenosineincreasetheeffectsofAchontheGABAergicneurons;AdenosinecounterD2receptoractivity;AdenosinereducesGABArelease.Ach:movementEnkephalinDynorphinPeptidemodulationofstriatalinputtotheglobuspollidus.EnkephalinPeptidemodulationPallidotomyandSubthalamotomy

PallidotomyandSubthalamotomySurgeryisusedinpeoplewithadvancedPDforwhomdrugtherapyisnolongersufficient.Becausetheseprocedurescausepermanentdestructionofbraintissue,theyhavelargelybeenreplacedbydeepbrainstimulation(DBS)fortreatmentofParkinson'sdisease.SurgeryisusedinpeoplewithDBSisprimarilyusedtostimulateoneofthreebrainregions:thesubthalamicnucleus,theglobuspallidus,orthethalamus.DBSisprimarilyusedtostimuResearchdirections

Animalmodels

Genetherapy(virus)Neuroprotectivetreatments

(GDNF)Neuraltransplantation

Stemcellstransplantshaveraisedgreatrecentinterest.Whentransplantedintothebrainsofrodentsandmonkeystheysurviveandimprovebehavioralabnormalities.Neverthelesswhilefetalstemcellsaretheeasiesttomanipulatetheiruseiscontroversial.Suchcontroversymaybeovercomewiththeuseofinducedpluripotentstemcellsfromadults.

ResearchdirectionsAnimalmodAschemeofthegenerationofinducedpluripotentstem(iPS)cells.

(1)Isolateandculturedonorcells.(2)Transfectstemcell-associatedgenesintothecellsbyviralvectors.Redcellsindicatethecellsexpressingtheexogenousgenes.(3)HarvestandculturethecellsaccordingtoEScellculture,usingmitoticallyinactivatedfeedercells(lightgray).(4)AsmallsubsetofthetransfectedcellsbecomeiPScellsandgenerateES-likecolonies.

Aschemeofthegenerationof主要講解的內(nèi)容:1．

基底神經(jīng)節(jié)的腦內(nèi)組成的核團(tuán)、它們的分布、主要通路的組成及其參與調(diào)節(jié)每條通路中的神經(jīng)遞質(zhì)及其功能。2．

基底神經(jīng)節(jié)（黑質(zhì)）損傷后的主要臨床表現(xiàn)及其病理表現(xiàn)的關(guān)系。3．PD腦內(nèi)黑質(zhì)多巴胺神經(jīng)元退化的機(jī)制研究。4．Parkinson’sDisease(PD)的治療方案及治療基礎(chǔ)。主要講解的內(nèi)容:思考題：1．Whatarethecomponentsofthebasalganglia?2．Howarethestructuresofthebasalgangliaconnected?3．Describethecorticostriatalprojections.4．Describetheconnectionsbetweensubthalamusandglobuspallidus.5．Describetheimportanceofthenigrastritalpathways.6．Whatistheroleofthebasalgangliainrelationtothemotorthalamus?7．Whataretheprincipalneurotransmittersandreceptorsassociatedwiththebasalganglia?8．Adisorderofthebasalgangliaisindicatedwhatsigns?9．Canadministrationofdopamine