Recent Advances in the cause and treatment of Parkinson：在帕金森的原因和治疗的最新进展

RecentAdvancesinthecauseandtreatmentof

Parkinsondisease

AnthonySchapiraHeadofDept.ClinicalNeurosciencesUCLInstituteofNeurologyUCLSOMEBACKGROUND…DeLau&BretelerLancetNeurol06AGEINGPathologicalchangesinPDDiseaseProgressionEvolutionofLewyBodyPathologyinPDAetiologyCAUSE-ENVIRONMENTEnvironmentalcausesofPDModifyingfactorsforPDriskPesticides,herbicides,farming,rurallivingSolventexposureDoctors,teachersRedhairLowvitaminDSmokingCoffeeNSAIDSIsradipineBlackhairHighurateEnvironment&GeneticsindiseaseENVIRONMENTGENETICSDISEASEEnvironment&GeneticsindiseaseENVIRONMENTGENETICSDISEASECAUSE-GENETICSGeneticcausesofPDGWAS

–SNCA,tau,HLA-DR2,LRRK2Alpha-synucleinmutations–point,multiplicationsParkinmutationsDJ1mutationsPINK1mutationsLRRK2mutationsOthers:HtrA2,UCHL1,ATP13A2,PLA2G6,GIGYF2Glucocerebrosidase:7-20foldincreasedriskPDPATHOGENESISMitochondriaProteinfolding,aggregation,propagationLysosomesBraakhypothesisforspreadofLewybodiesBraaketcoll.,2003KordoweretalNatMed2008FetalgraftcellsdevelopPDpathologyKordoweretalNatMed2008FetalgraftcellsdevelopPDpathologyPDPATHOGENESISMitochondriaProteinfolding,aggregation,propagationLysosomesGlucocerebrosidaseAuR,>300mutations,↓GBAactivityGaucherdisease,lysosomalenzymeCommonestinAshkenaziJewsTypicalPD,meanageonset55y,FHin24%*Lewybodypositive:4.5foldincreaseinGBAmutationsinLB-PDinQSPDBB(NeumannBrain2009)LifetimeriskforPDinGDpatients~20x(BultronJInhMetDis2010)GCaseinPDBrain58%*↓GCaseinGBAmutationpositiveSNc48%*↓GCaseinGBAmutationpositivestriatum*p<0.01GCaseinPDBrain58%*↓GCaseinGBAmutationpositiveSNc48%*↓GCaseinGBAmutationpositivestriatum33%*↓GCaseinGBAmutationnegativesporadicPDSNc*p<0.01TheGCase-alpha-synucleinconnection↑SNCA↓GCase↓SNCA↑GCaseSchapiraLancet2014SymptomatictreatmentsforParkinsondiseaseDrugtreatmentofParkinson’sdiseaseL-dopaDecarboxylaseinhibitors–carbidopa,benserazideMAO-Binhibitors–selegiline,rasagilineCOMTinhibitors–entacapone,tolcaponeCombinationforms–StalevoControlledrelease–SinemetCRDispersible–MadopardispersibleLiquidformulations–L-dopamethylesterIntraduodenaladministration-DuoDopaRopinirolePramipexolePergolideBromocriptineCabergolineExtendedrelease–RequipXLTransdermaladministration–NeuProSubcutaneousinfusion-apomorphineSafinamideReversibleMAOBinhibitorMayhaveNa-channel,anti-glutamatergicactivityOncedaily50-100mgAdjuncttolevodopa(+)ordopamineagonistReducesOFF-time,improvesON-timewithoutincreasingtroublesomedyskinesia.Non-dopaminergicapproachestothetreatmentofParkinson’sdiseaseMotorsymptoms–amantadine,anticholinergicsDementia–cholinesteraseinhibitorsPsychosis–atypicalantipsychoticsNeuropsychiatric–anxiolytics,antidepressantsSomnolence–modafinilAutonomicsigns–mineralocorticosteroids,oxybutyninnNeuroprotectionSlowingthecourseofParkinsondiseasePotentialtherapeutictargetsMitochondria:CoQ+/-vitE,creatine,PGC-1α,rasagiline,exenetideAnti-oxidants:Fe-chelators,inosineLRRK2kinaseinhibitorsGrowthfactorstimulants:GDNF,BDNFAutophagy/mitophagystimulants:rapamycinProteindisaggregationCalciumchannelmodulators:isradipineSNCAmodulatorsGBAenhancers–chaperonesSchapiraLancet2014TheGCase-alpha-synucleinconnection↑SNCA↓GCase↓SNCA↑GCase↓TOXICITYGBAsiRNA,CBE,GBA-KOmice,PDbrainSNCAo/ecells,PDtriplicationcells,PDbrainAAV-GBASchapiraLancet2014Schapira&GeggPNAS2013GCase-alpha-synucleinasatargetforPDHypothesisIncreasingGCaseactivitywillreduceSNCAlevelsandslowtheprogressionofPDThisw