2017年帕金森病十大研究进展

2017年帕金森病十大研究进展2017年帕金森病十大研究进展第一位：Nature报道α-synuclein可能是引起PD中T细胞免疫异常的关键抗原，提示PD的发生可能与自身免疫机制相关。Sulzeretal.TcellsfrompatientswithParkinson'sdiseaserecognizeα-synucleinpeptides.Nature.2017Jun29;546(7660):656-661.AbstractGeneticstudieshaveshowntheassociationofParkinson'sdiseasewithallelesofthemajorhistocompatibilitycomplex.Hereweshowthatadefinedsetofpeptidesthatarederivedfromα-synuclein,aproteinaggregatedinParkinson'sdisease,actasantigenicepitopesdisplayedbytheseallelesanddrivehelperandcytotoxicTcellresponsesinpatientswithParkinson'sdisease.TheseresponsesmayexplaintheassociationofParkinson'sdiseasewithspecificmajorhistocompatibilitycomplexalleles.第二位：Lancet临床试验证实糖尿病治疗药物Exenatide（GLP-1激动剂）可以用于治疗帕金森病Athaudaetal.ExenatideonceweeklyversusplaceboinParkinson'sdisease:arandomised,double-blind,placebo-controlledtrial.Lancet.2017Oct7;390(10103):1664-1675.AbstractBACKGROUND:Exenatide,aglucagon-likepeptide-1(GLP-1)receptoragonist,hasneuroprotectiveeffectsinpreclinicalmodelsofParkinson'sdisease.Weinvestigatedwhethertheseeffectswouldbeapparentinaclinicaltrial.METHODS:Inthissingle-centre,randomised,double-blind,placebo-controlledtrial,patientswithmoderateParkinson'sdiseasewererandomlyassigned(1:1)toreceivesubcutaneousinjectionsofexenatide2mgorplaceboonceweeklyfor48weeksinadditiontotheirregularmedication,followedbya12-weekwashoutperiod.Eligiblepatientswereaged25-75years,hadidiopathicParkinson'sdiseaseasmeasuredbyQueenSquareBrainBankcriteria,wereondopaminergictreatmentwithwearing-offeffects,andwereatHoehnandYahrstage2·5orlesswhenontreatment.Randomisationwasbyweb-basedrandomisationwithatwostratablockdesignaccordingtodiseaseseverity.Patientsandinvestigatorsweremaskedtotreatmentallocation.TheprimaryoutcomewastheadjusteddifferenceintheMovementDisordersSocietyUnifiedParkinson'sDiseaseRatingScale(MDS-UPDRS)motorsubscale(part3)inthepracticallydefinedoff-medicationstateat60weeks.Allefficacyanalyseswerebasedonamodifiedintention-to-treatprinciple,whichincludedallpatientswhocompletedanypost-randomisationfollow-upassessments.ThestudyisregisteredatClinicalTrials.gov(NCT01971242)andiscompleted.FINDINGS:BetweenJune18,2014,andMarch13,2015,62patientswereenrolledandrandomlyassigned,32toexenatideand30toplacebo.Ourprimaryanalysisincluded31patientsintheexenatidegroupand29patientsintheplacebogroup.At60weeks,off-medicationscoresonpart3oftheMDS-UPDRShadimprovedby1·0points(95%CI-2·6to0·7)intheexenatidegroupandworsenedby2·1points(-0·6to4·8)intheplacebogroup,anadjustedmeandifferenceof-3·5points(-6·7to-0·3;p=0·0318).Injectionsitereactionsandgastrointestinalsymptomswerecommonadverseeventsinbothgroups.Sixseriousadverseeventsoccurredintheexenatidegroupandtwointheplacebogroup,althoughnoneineithergroupwerejudgedtoberelatedtothestudyinterventions.INTERPRETATION:Exenatidehadpositiveeffectsonpracticallydefinedoff-medicationmotorscoresinParkinson'sdisease,whichweresustainedbeyondtheperiodofexposure.Whetherexenatideaffectstheunderlyingdiseasepathophysiologyorsimplyinduceslong-lastingsymptomaticeffectsisuncertain.ExenatiderepresentsamajornewavenueforinvestigationinParkinson'sdisease,andeffectsoneverydaysymptomsshouldbeexaminedinlonger-termtrials.FUNDING:MichaelJFoxFoundationforParkinson'sResearch.第三位：人类iPSC来源的多巴胺能神经元移植首次在灵长类动物中获得成功。Kikuchietal.HumaniPScell-deriveddopaminergicneuronsfunctioninaprimateParkinson'sdiseasemodel.Nature.2017Aug30;548(7669):592-596.AbstractInducedpluripotentstemcells(iPScells)areapromisingsourceforacell-basedtherapytotreatParkinson'sdisease(PD),inwhichmidbraindopaminergicneuronsprogressivelydegenerate.However,long-termanalysisofhumaniPScell-deriveddopaminergicneuronsinprimatePDmodelshasneverbeenperformedtoourknowledge.HereweshowthathumaniPScell-deriveddopaminergicprogenitorcellssurvivedandfunctionedasmidbraindopaminergicneuronsinaprimatemodelofPD(Macacafascicularis)treatedwiththeneurotoxinMPTP.Score-basedandvideo-recordinganalysesrevealedanincreaseinspontaneousmovementofthemonkeysaftertransplantation.Histologicalstudiesshowedthatthematuredopaminergicneuronsextendeddenseneuritesintothehoststriatum;thiseffectwasconsistentregardlessofwhetherthecellswerederivedfrompatientswithPDorfromhealthyindividuals.CellssortedbythefloorplatemarkerCORINdidnotformanytumoursinthebrainsforatleasttwoyears.Finally,magneticresonanceimagingandpositronemissiontomographywereusedtomonitorthesurvival,expansionandfunctionofthegraftedcellsaswellastheimmuneresponseinthehostbrain.Thus,thispreclinicalstudyusingaprimatemodelindicatesthathumaniPScell-deriveddopaminergicprogenitorsareclinicallyapplicableforthetreatmentofpatientswithPD.第四位：Science研究揭示了多巴胺氧化在耦联线粒体和溶酶体功能障碍中的关键作用，提示氧化应激可能是引起多巴胺能神经元变性的起始步骤。Burbullaetal.DopamineoxidationmediatesmitochondrialandlysosomaldysfunctioninParkinson'sdisease.Science.2017Sep22;357(6357):1255-1261.AbstractMitochondrialandlysosomaldysfunctionhavebeenimplicatedinsubstantianigradopaminergicneurodegenerationinParkinson'sdisease(PD),buthowthesepathwaysarelinkedinhumanneuronsremainsunclear.Herewestudieddopaminergicneuronsderivedfrompatientswithidio