_Synuclein蛋白聚集状态与帕金森病形成_王丹晨

ISSN1007-7626CN11-3870PQChineseJournalofBiochemistryandMolecularBiology2006822(8):615~620#综述#A-Synuclein王丹晨,于珊珊,刘巍峰*,陈冠军(山东大学生命科学学院,济南250100)帕金森病是一种常见的老年神经退行性疾病,其致病机理复杂.其中A-synuclein基因是较早发现的与帕金森病相关的基因,其编码的A-synuclein蛋白是帕金森病神经元内出现的一种蛋白包涵体结构)))路易体的主要组成成分.最近的研究结果显示,A-synuclein蛋白存在不同聚集状态间的转换,其中聚集过程中形成的寡聚体中间构象具有较强的细胞毒性,可能对帕金森病的发病过程有着重要作用;而且这种聚集状态的转换过程受到多种遗传学与细胞学因素的影响,从而在某种程度上反映了帕金森病发生形成的遗传学与细胞学机制.本文将对A-synuclein蛋白聚集状态转换特性及其在帕金森病发病过程中作用机制方面的研究进展作一综述.帕金森病;A-synuclein蛋白;蛋白聚集;不饱和脂肪酸;泛素-蛋白酶体Q71;Q426AggregationStatesofA-SynucleinandItsInvolvementinParkinson.sDiseaseWANGDan-Chen,YUShan-Shan,LIUWe-iFeng*,CHENGuan-Jun(SchoolofLifeSciences,ShandongUniversity,Jinan250100,China)AbstractParkinson.sdisease(PD)isawide-spreadage-relatedneurodegenerationdisorderwithverycomplexpathologicalmechanisms.A-SynucleingeneisamongthefirstgenesidentifiedtoberelatedtoPDandtheA-synucleinproteinisamajorcomponentofproteininclusionscalledLewybodies,whoseappearanceinthesurvivaldopamineneuronsisoneofthepathologichallmarksofPD.A-synucleinhasrecentlybeenshowntoundergotransitionsbetweendifferentaggregationstatesbothinvivoandinvitro,mediatedbythereadilyaggregatedpropensityofA-synuclein.Amongothers,anintermediateoligomerconfigurationcalledprotofibril,hasbeenfoundtoshowmuchstrongercytotoxicitythantheinsolublefibrilconformation,whichisthefinalformofpolymerizationnormallyfoundinLewybodies.Inthemeantime,quiteafewgeneticandcellularfactorsincludingA-synucleingenemutationandduplication,lipidmetabolism,oxidativestressaswellasproteinfoldingandqualitycontrolsystem,havebeendemonstratedtoaffecttheprocessofA-synucleinaggregation.ThesefindingsarebeginningtouncovertheunderlyingmechanismsoftheoccurrenceanddevelopmentofPD.Herein,wereviewrecentfindingsonthestructuralcharacterizationofA-synucleinandexploitthepossiblemolecularandcellularmechanismsinvolvedintheetiopathogenesisofPD.KeywordsParkinson.sdisease;A-synuclein;proteinaggregation;unsaturatedfattyacid;ubiquitinandproteosome:2006-03-10,:2006-05-09(2004B302011)*Tel:[phone];Fax:[phone];E-mail:[e-mail]:March10,2006;Accepted:May9,2006SupportedbyaResearchGrantforOutstandingYoungScientistsofShandongProvince*Correspondingauthor:Tel:[phone];Fax:[phone];E-mail:[e-mail](Parkinson.sdisease,PD),40,011%.,,,,[1~4,34].,(substantianigraparscompacta,SNC).,60%[2];SNC(Lewybodies,LBs)(Lewyneurites),.,10[3].,20%~30%,,.,.,10~14nm,A-synuclein[4],.,,LBs;,A-synuclein.,10,A-synuclein,A53T,A30P32A-synuclein,(parkin,uch-l1)[5];,A-synuclein[6,7].A-synuclein.1A-SynucleinSynuclein,315~20kDA-,B-C-synuclein.,A-synucleinB-synuclein,C-synuclein[8].,A-synuclein.,A-synuclein,,N2P3,;,A-synuclein,A[9].A-Synuclein,.,A-synuclein[10].A-synuclein,,;[11].A-synuclein,A-synuclein.,A-synuclein,[12].A-synuclein,PLD2,[44].,,A(cysteine-stringprotein-A,CSPA),A-synuclein,SNARE(solubleNSF-attachmentproteinreceptorcomplex,SNARE),A-synuclein[14].,A-synuclein,A-synuclein,(protofibrils)A-synuclein.,B.,,20~30A-synuclein;,(fibrilousstructure)[15,16].,A-synucleinA53TA30P,,A30PA53T[17].A-synuclein,A-synuclein.,,A-synuclein[18,19];,A-synuclein[20].,61622,PI3SH3HypFN,,,[21,22].Sharon[23](MES),A-synuclein;,A-synucleinA53T,A-synuclein;,Sharon[23]MES,A-synuclein,.MES1h,A-synuclein,;.,[3]:,,.,A-synuclein.2A-synucleinA-Synuclein,,,A-synuclein.,A-synuclein,parkin26SUCHL-1.,(Hsp70Hsp40),,Hsp70A-synuclean;Hsp70,Grp78[24].,A-synuclean.A-synuclein,2,parkinuch-l1,.,4.465,parkinN,CE3.E3E1E2,,26S[25].,parkinE3,parkin.A-synucleinparkin,parkin,A-synucleinDAparkin[26];,parkinA-synuclein,A-synucleinLBA-synuclein[27].,parkinA-synuclein.,A-synuclein,,[25,28].,ParkinA-synuclein,A-synuclein,.uch-l1C-L1(ubiquitinC-terminalhydrolyase-L1,UCH-L1),2%,.,.A-synuclein.,,A-synuclein.,,A-synulein,A-synuleinA53TA30P,,,,[29].6178:A-Synuclein3A-SynucleinA-Synuclein,.,[30],10%;,.,,,A-synucleinparkinuch-l13,,A-synucleinuch-l1,parkin.A-synuclein,ContursiGreek.,A-synuclein209(A53T).,A-synuclein(A30P)[5].,A-synucleinA-synuclein.,,A-synuclein,A-synuclein;,A-synuclein,A-synuclein,[31,13].,,A-synuclein,.,[32].,A-synuclein,2.2[33~35].,Ñ,.,Ñ,MPTP(paraquat)Retenone,A-synuclein,Ñ[35].,ÑNADH(T-A)[36].,A-synucleinÑ,A-synucleinMPTP[37];Ñ))),.MPTP,,,Ñ.,[38],A-synucleinDNA,,[43].,,,.,A-synuclein[11,12],,A-synuclein.,,,.,A-synuclein.,LBA-synuclein,,A-synuclein,[39,40];,,A-synuclein,A-synuclein[41].,,,,[Fig.1].,,,A-synuclein,,(quality61822Fig.1TwohypotheticmodelsabouttheinvolvementoffreeradicalsinthedevelopmentofParkinson.sdisease[42]control,QC).,A-synuclein;,A-synuclein,(Alzhimer.sdiseaseHuntington.sdisease),.,A-synuclein,A-synuclein[44].(References)[1]LansburyPTJr,BriceA.GeneticsofParkinson.sdiseaseandbiochemicalstudiesofimplicatedgeneproducts[J].CurrOpinCellBiol,2002,14(5):653-660[2]LothariusJ,BrundinP.PathogenesisofParkinson.sdisease:dopamine,vesiclesandalpha-synuclein[J].NatRevNeurosci,2002,3(12):932-942[3]GoldbergMS,LansburyPTJr.Isthereacause-and-effectrelationshipbetweenalpha-synucleinfibrillizationandParkinson.sdisease[J]?NatCellBiol,2000,2(7):E115-E119[4]Goe