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α-synuclein蛋白及抑制剂对酪氨酸酶的调控机制.docx

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α-synuclein蛋白及抑制剂对酪氨酸酶的调控机制 Introduction α-synucleinisaproteinthatismainlyexpressedinthenervoussystem,anditsaccumulationinneuronshasbeenimplicatedinthepathogenesisofneurodegenerativedisorderssuchasParkinson'sdisease(PD).α-synucleinisknowntointeractwithmultipleproteins,andoneoftheseproteinsistyrosinehydroxylase(TH),animportantenzymeinvolvedinthesynthesisofcatecholamines.However,themechanismbywhichα-synucleinregulatesTHactivityisnotfullyunderstood.Inthispaper,weaimtoreviewthecurrentliteratureontheregulatorymechanismsofα-synucleinonTHactivity,aswellasthepotentialofα-synucleininhibitorsastherapeutictargetsforPD. RegulationofTHactivitybyα-synuclein THistherate-limitingenzymeinthesynthesisofcatecholamines(dopamine,norepinephrine,andepinephrine).THactivityisknowntoberegulatedbymultiplefactors,includingfeedbackinhibitionbycatecholamines,stimulatoryeffectsofcofactorssuchastetrahydrobiopterinandiron,aswellaspost-translationalmodificationssuchasphosphorylationandnitration.α-synucleinhasbeenshowntointeractwithTH,andthisinteractionhasbeenreportedtobothenhanceandinhibitTHactivity. Severalstudieshavereportedthatα-synucleincanfunctionasapositiveregulatorofTHactivity.Forexample,Dasandcolleaguesshowedthatα-synucleinpromotesTHactivitybystabilizingtheenzyme'stetramerconformation,whichisimportantforitscatalyticactivity(Dasetal.,2013).Inaddition,α-synucleinhasbeenshowntoenhanceTHactivitybyservingasachaperoneproteinthatfacilitatesthetransportofTHintodopaminergicneurons(Kimetal.,2014).Furthermore,α-synucleinhasbeenreportedtoregulatetheintracellulartraffickingofTHbypromotingitstranslocationfromtheendoplasmicreticulumtotheGolgiapparatus(Xuetal.,2019). Ontheotherhand,thereisalsoevidencethatα-synucleincanactasanegativeregulatorofTHactivity.Forinstance,α-synucleinhasbeenshowntoinhibitthephosphorylationofTHatSer40,amodificationthatisknowntoactivatetheenzyme(Zhouetal.,2019).Inaddition,α-synucleinhasbeenreportedtoinhibitTHactivitybyinterferingwithitsbindingtoitscofactortetrahydrobiopterin(THB)(Rco