결론

지질 래프트에 존재하는 UCH-L1 단백질은 타이로신-인산화 반응의 영향을 받아 지질 래프트로 이동하는데 관련이 되어 있다는 것을 확인 했지만 UCH-L1단백 질이 직접적으로 타이로신-인산화 되어 발생하는 것은 아니다.타이로신-인산화 반응 의 영향을 받아 지질 래프트로 이동한 UCH-L1 단백질은 지질 래프트의 신호변화를 야기할 것이라 추측된다.

참고문헌

1. AbramiL,vanDerGootFG:Plasmamembranemicrodomainsactas concentrationplatformstofacilitateintoxicationbyaerolysin.J CellBiol 147:175-184,1999

2. AntelmiE,CardoneRA,GrecoMR,RubinoR,DiSoleF,MartinoNA, CasavolaV,CarcangiuM,MoroL,ReshkinSJ:ss1integrinbinding phosphorylatesezrinatT567toactivatealipidraftsignalsomedriving invadopodiaactivityandinvasion.PLoS One8:e75113,2013

3. BickelPE,SchererPE,SchnitzerJE,OhP,LisantiMP,LodishHF:Flotillin andepidermalsurfaceantigendefineanew familyofcaveolae-associated integralmembraneproteins.JBiolChem 272:13793-13802,1997

4. CarmineBelinA,WesterlundM,BergmanO,NissbrandtH,LindC,Sydow O,GalterD:S18Y inubiquitincarboxy-terminalhydrolaseL1(UCH-L1) associatedwithdecreasedriskofParkinson'sdiseaseinSweden.

Parkinsonism RelatDisord13:295-298,2007

5. CartierAE,UbhiK,SpencerB,Vazquez-RoqueRA,KosbergKA,Fourgeaud L,KanaysonP,PatrickC,RockensteinE,PatrickGN,MasliahE:

DifferentialeffectsofUCHL1modulationonalpha-synucleininPD-like modelsofalpha-synucleinopathy.PLoS One7:e34713,2012

6. ChenG,HoweAG,XuG,FrohlichO,KleinJD,SandsJM:Mature N-linkedglycansfacilitateUT-A1ureatransporterlipidraft compartmentalization.FASEB J25:4531-4539,2011

7. ColeRN,HartGW:CytosolicO-glycosylationisabundantinnerve

terminals.J Neurochem 79:1080-1089,2001

8. CostesS,Huang CJ,GurloT,DavalM,MatveyenkoAV,RizzaRA,Butler AE,ButlerPC:beta-celldysfunctionalERAD/ubiquitin/proteasomesystem in type2diabetesmediatedbyisletamyloidpolypeptide-inducedUCH-L1 deficiency.Diabetes60:227-238,2011

9. DawsonTM,KoHS,DawsonVL:GeneticanimalmodelsofParkinson's disease.Neuron66:646-661,2010

10. ElbazA,BowerJH,PetersonBJ,MaraganoreDM,McDonnellSK,Ahlskog JE,SchaidDJ,RoccaWA:SurvivalstudyofParkinsondiseaseinOlmsted County,Minnesota.ArchNeurol60:91-96,2003

11. FallonL,MoreauF,CroftBG,LabibN,GuWJ,FonEA:Parkinand CASK/LIN-2associateviaaPDZ-mediatedinteractionandareco-localized

14. FortinDL,TroyerMD,NakamuraK,KuboS,AnthonyMD,EdwardsRH:

Lipidraftsmediatethesynapticlocalizationofalpha-synuclein.J Neurosci 24:6715-6723,2004

15. FriedrichsonT,KurzchaliaTV:MicrodomainsofGPI-anchoredproteinsin livingcellsrevealedbycrosslinking.Nature394:802-805,1998

16. FrisanT,CoppotelliG,DryseliusR,MasucciMG:UbiquitinC-terminal

hydrolase-L1interactswithadhesioncomplexesandpromotescellmigration, survival,andanchorageindependentgrowth.FASEB J26:5060-5070,2012 17. GuglielmottoM,MonteleoneD,BoidoM,PirasA,GilibertoL,BorghiR,

VercelliA,FornaroM,TabatonM,TamagnoE:Abeta1-42-mediated down-regulationofUch-L1isdependentonNF-kappaB activationand impairedBACE1lysosomaldegradation.Aging Cell11:834-844,2012 18. HatanoT,KuboS,ImaiS,MaedaM,IshikawaK,MizunoY,HattoriN:

Leucine-richrepeatkinase2associateswithlipidrafts.Hum MolGenet16:

678-690,2007

19. HayashiH,IgbavboaU,HamanakaH,KobayashiM,FujitaSC,WoodWG, YanagisawaK:Cholesterolisincreasedintheexofacialleafletofsynaptic plasmamembranesofhumanapolipoproteinE4knock-inmice.Neuroreport 13:383-386,2002

20. IgbavboaU,EckertGP,MaloTM,StudniskiAE,JohnsonLN,Yamamoto N,KobayashiM,FujitaSC,AppelTR,MullerWE,WoodWG,Yanagisawa K:Murinesynaptosomallipidraftproteinandlipidcompositionarealtered byexpressionofhumanapoE 3and4andbyincreasingage.JNeurolSci 229-230:225-232,2005

21. IlangumaranS,HoessliDC:Effectsofcholesteroldepletionbycyclodextrin onthesphingolipidmicrodomainsoftheplasmamembrane.Biochem J335(

Pt2):433-440,1998

22. KabutaT,FurutaA,AokiS,FurutaK,WadaK:Aberrantinteraction betweenParkinsondisease-associatedmutantUCH-L1andthelysosomal receptorforchaperone-mediatedautophagy.JBiolChem 283:23731-23738, 2008

23. Kim KS,Kim JS,ParkJY,SuhYH,JouI,JoeEH,ParkSM:DJ-1 associateswithlipidraftsbypalmitoylationandregulateslipid

rafts-dependentendocytosisinastrocytes.Hum MolGenet22:4805-4817, 2013

24. KitadaT,AsakawaS,HattoriN,MatsumineH,YamamuraY,Minoshima S,YokochiM,MizunoY,ShimizuN:Mutationsintheparkingenecause autosomalrecessivejuvenileparkinsonism.Nature392:605-608,1998 25. KoradeZ,KenworthyAK:Lipidrafts,cholesterol,andthebrain.

Neuropharmacology55:1265-1273,2008

26. LangAE,LozanoAM:Parkinson'sdisease.Firstoftwoparts.N EnglJ Med339:1044-1053,1998

27. LiX,StandleyC,SappE,ValenciaA,QinZH,KegelKB,YoderJ,

Comer-TierneyLA,EstevesM,ChaseK,AlexanderJ,MassoN,SobinL, BellveK,TuftR,LifshitzL,FogartyK,AroninN,DiFigliaM:Mutant huntingtinimpairsvesicleformationfrom recyclingendosomesbyinterfering withRab11activity.MolCellBiol29:6106-6116,2009

28. LiuY,FallonL,LashuelHA,LiuZ,LansburyPT,Jr.:TheUCH-L1gene encodestwoopposing enzymaticactivitiesthataffectalpha-synuclein degradationandParkinson'sdiseasesusceptibility.Cell111:209-218,2002 29. LiuZ,MerayRK,GrammatopoulosTN,FredenburgRA,CooksonMR,Liu Y,LoganT,LansburyPT,Jr.:Membrane-associatedfarnesylatedUCH-L1 promotesalpha-synucleinneurotoxicityandisatherapeutictargetfor Parkinson'sdisease.ProcNatlAcadSciU S A 106:4635-4640,2009 30. MadoreN,SmithKL,Graham CH,JenA,BradyK,HallS,MorrisR:

FunctionallydifferentGPIproteinsareorganizedindifferentdomainsonthe

neuronalsurface.EMBO J 18:6917-6926,1999

31. MaraganoreDM,FarrerMJ,HardyJA,LincolnSJ,McDonnellSK,Rocca WA:Case-controlstudyoftheubiquitincarboxy-terminalhydrolaseL1 geneinParkinson'sdisease.Neurology53:1858-1860,1999

32. MartinI,DawsonVL,DawsonTM:Recentadvancesinthegeneticsof Parkinson'sdisease.AnnuRevGenomicsHum Genet12:301-325,2011 33. MatsuzakiK:[Gangliosidecluster-mediatedaggregationandcytotoxicityof

36. Molander-MelinM,Blennow K,BogdanovicN,DellhedenB,ManssonJE, FredmanP:StructuralmembranealterationsinAlzheimerbrainsfoundtobe associatedwithregionaldiseasedevelopment;increaseddensityof

gangliosidesGM1andGM2andlossofcholesterolindetergent-resistant membranedomains.JNeurochem 92:171-182,2005

37. NaslavskyN,SteinR,YanaiA,FriedlanderG,TaraboulosA:

Characterizationofdetergent-insolublecomplexescontainingthecellular prionproteinanditsscrapieisoform.JBiolChem 272:6324-6331,1997 38. Neumann-GiesenC,FalkenbachB,BeichtP,ClaasenS,LuersG,Stuermer

CA,HerzogV,TikkanenR:Membraneandraftassociationof

reggie-1/flotillin-2:roleofmyristoylation,palmitoylationandoligomerization andinductionoffilopodiabyoverexpression.Biochem J378:509-518,2004 39. NishikawaK,LiH,KawamuraR,OsakaH,Wang YL,HaraY,HirokawaT,

ManagoY,AmanoT,NodaM,AokiS,WadaK:Alterationsofstructure andhydrolaseactivityofparkinsonism-associatedhumanubiquitin

carboxyl-terminalhydrolaseL1variants.Biochem BiophysResCommun 304:176-183,2003

40. ObesoJA,Rodriguez-OrozMC,RodriguezM,LanciegoJL,ArtiedaJ,Gonzal N,Olanow CW:PathophysiologyofthebasalgangliainParkinson'sdisease. TrendsNeurosci23:S8-19,2000

41. OpazoF,KrenzA,HeermannS,SchulzJB,FalkenburgerBH:Accumulation andclearanceofalpha-synucleinaggregatesdemonstratedbytime-lapse imaging.J Neurochem 106:529-540,2008

42. OzhanG,SezginE,WehnerD,PfisterAS,KuhlSJ,Kagermeier-SchenkB,

44. PoonWW,CarlosAJ,AguilarBL,BerchtoldNC,KawanoCK,Zograbyan V,YaoprukeT,ShelanskiM,CotmanCW:beta-Amyloid(Abeta)oligomers impairbrain-derivedneurotrophicfactorretrogradetrafficking by

down-regulatingubiquitinC-terminalhydrolase,UCH-L1.JBiolChem 288:

16937-16948,2013

45. RathorN,Zhuang R,WangJY,DonahueJM,TurnerDJ,RaoJN:

Src-mediatedcaveolin-1phosphorylationregulatesintestinalepithelial restitutionbyalteringCa2+influx afterwounding.Am J Physiol GastrointestLiverPhysiol306:G650-658,2014

46. RushworthJV,HooperNM:LipidRafts:LinkingAlzheimer'sAmyloid-beta Production,Aggregation,andToxicityatNeuronalMembranes.IntJ AlzheimersDis2011:603052,2010

47. SatoK,TanabeC,YonemuraY,WatahikiH,ZhaoY,YagishitaS,EbinaM, SuoS,FutaiE,MurataM,IshiuraS:Localizationofmatureneprilysinin

50. SetsuieR,Wang YL,MochizukiH,OsakaH,HayakawaH,IchiharaN,Li H,FurutaA,SanoY,SunYJ,KwonJ,KabutaT,YoshimiK,AokiS, MizunoY,NodaM,WadaK:Dopaminergicneuronallossintransgenicmice expressingtheParkinson'sdisease-associatedUCH-L1I93M mutant.

53. StocchiF:PathologicalgamblinginParkinson'sdisease.LancetNeurol4:

590-592,2005

54. StoreySM,GibbonsTF,WilliamsCV,ParrRD,SchroederF,BallJM:

Full-length,glycosylatedNSP4islocalizedtoplasmamembranecaveolaeby anovelraftisolationtechnique.JVirol81:5472-5483,2007

55. TaylorDR,HooperNM:Thelow-densitylipoproteinreceptor-related protein1(LRP1)mediatestheendocytosisofthecellularprionprotein.

Biochem J402:17-23,2007

56. TodaT,MomoseY,MurataM,TamiyaG,YamamotoM,HattoriN,Inoko H:TowardidentificationofsusceptibilitygenesforsporadicParkinson's disease.JNeurol250Suppl3:III40-43,2003

57. TofarisGK,SpillantiniMG:Physiologicalandpathologicalpropertiesof alpha-synuclein.CellMolLifeSci64:2194-2201,2007

58. UverskyVN:Neuropathology,biochemistry,andbiophysicsof alpha-synucleinaggregation.JNeurochem 103:17-37,2007

59. ValapalaM,VishwanathaJK:Lipidraftendocytosisandexosomaltransport facilitateextracellulartrafficking ofannexinA2.JBiolChem 286:

30911-30925,2011

60. ValenciaA,ReevesPB,SappE,LiX,AlexanderJ,KegelKB,ChaseK, AroninN,DiFigliaM:Mutanthuntingtinandglycogensynthasekinase 3-betaaccumulateinneuronallipidraftsofapresymptomaticknock-in mousemodelofHuntington'sdisease.JNeurosciRes88:179-190,2010 61. WilkinsonKD,LeeKM,DeshpandeS,Duerksen-HughesP,BossJM,Pohl

J:Theneuron-specificproteinPGP 9.5isaubiquitincarboxyl-terminal hydrolase.Science246:670-673,1989

62. WirdefeldtK,AdamiHO,ColeP,TrichopoulosD,MandelJ:Epidemiology

andetiologyofParkinson'sdisease:areview oftheevidence.EurJ Epidemiol26Suppl1:S1-58,2011

63. Zheng YZ,BergKB,FosterLJ:Mitochondriadonotcontainlipidrafts,and lipidraftsdonotcontainmitochondrialproteins.J LipidRes50:988-998, 2009

64. ZlatkineP,MehulB,MageeAI:Retargetingofcytosolicproteinstothe plasmamembranebytheLckproteintyrosinekinasedualacylationmotif.J CellSci110(Pt5):673-679,1997

ABSTRACT

-Thel ocal i zat i on ofUCH-L1( Ubi qui t i n C-t er mi nal Hydr ol ase-L1)i n l i pi dr af t sofneur onalcel l

JinsuKim

NeuroscienceGraduateProgram DepartmentofBiomedicalSciences TheGraduateSchool,AjouUniversity

(SupervisedbySang MyunPark,M.D.,Ph.D.)

Parkinson's disease(PD)is the progressive neurodegenerative disorderthat profoundly affects movement,and is characterized by dopaminergic neuronalloss in the substantia nigra,midbrain.Symtoms ofPD are resting tremor,rigidity, postural instability and slowness of movement. Lipid rafts enriched glycosylphosphatidylinositol (GPI)-anchored proteins, glycosphingolipid and cholresterol, are specialized microdomains that play a role in endocytosis, exocytosis,signaltransduction andreceptortrafficking.Thedisruption oflipid raft from alteration ofgangliosidesand cholesterolcontenthasbeen reported to cause neurodegenerative disorders such as Alzheimer's disease(AD), Parkinson's disease(PD), Huntington's disease(HD) and Prion's disease and it has been reported thatPD-associated genes such as α-synuclein,LRRK2,PINK1,Parkin,

and DJ-1 as wellas AD-associated gene,amyloid-β,Prion's disease-associated phosphorylation.But,thetyrosinephosphorylation ofUCH-L1mightnotaffecton its loclization oflipid rafts directly.The localization ofUCH-L1 into lipid raft