內(nèi)質(zhì)網(wǎng)關(guān)聯(lián)降解通路對神經(jīng)退行性疾病致病蛋白的降解調(diào)控.pdf

1、中國科學(xué)技術(shù)大學(xué)博士學(xué)位論文內(nèi)質(zhì)網(wǎng)關(guān)聯(lián)降解通路對神經(jīng)退行性疾病致病蛋白的降解調(diào)控姓名：應(yīng)征申請學(xué)位級別：博士專業(yè)：神經(jīng)生物學(xué)指導(dǎo)教師：王光輝20091001ABSTRACTABSTRACTThehallmarkofmanyneurodegenerativedisorders，suchasAlzheimer’Sdisease(AD)，Parkinson’Sdisease(PD)，amyotrophiclateralsclerosis(AL

2、S)，polyglutaminediseasesandpriondiseasesandfamilialencephalopathywithneuroserpininclusionbodies(FENIB)，istheintracellularaggregatesformedbytheaccumulationofaberrantmisfoldeddiseaseproteinsMutationsoftheseproteinsmayalter

3、theconformationandresultintheirmisfoldingFurthermore，thesemisfoldedproteinsCallformaggregateswhicharehighlyubiquitinated，alongwithmolecularchaperonesandproteasomesubunits’Copperzincsuperoxidedismutase(SOD1)isanantioxidan

4、tenzymeMutationsofSOD1areassociatedwithALSAtaxin3isanotherneurodegenerativediseaseproteininassociationwithMachado—Josephdisease(alsoknownasspinocerebellarataxiatype3，SCA3)Thesetwodiseaseproteinsalemisfolded，aggregatedand

5、neurotoxicindiseasedbrains。ItwasrecentlyreportedthatthesetwoproteinsareassociatedwithER(endoplasmicreticulum)andbothofthemareinvolvedinERAD(ERassociateddegradation)AbnormalaccumulationofthemintheERinducesERstressERADisap

6、roteinqualitycontrolsystemineukaryotestodegrademisfoldedproteinsintheERInERADprocess，misfoldedorunassembledtargetproteinsareselectedassubstratesandfinallydegradedbythecytoplasmic26Sproteasomethroughubiquitinproteasomesys

7、tem(UPS)Manyunassembledormisfolded’proteinsareaccumulatedintheERanddegradedthroughERADUbiquitinligase(E3)mediatedubiquitinationofproteinsisanimportantprocessforproteindegradationbyERADsystemUptodate，alleastfiveE3s，includ

8、inggp78andHrdl，havebeenidentifiedtobeinvolvedinmammalianERADSimilartootherERADE3s，mammaliangp78isanERmembrane—spanningproteinwiththeRINGfingertypeubiquitinligaseactivitysitethatislocalizedontheERsurfacetowardsthecytoplas

9、micsideInthisthesis，wemainlyexploredtheroleofERADinALSandSCA3／MJDprocessWeshowthatgp78interactswithbothSODIandataxin3Overexpressionofgp78promotestheubiquitinationanddegradationofthesetwoproteins，whereasknockdownofgp78sta