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1、REVIEWSTargetingproteinaggregationforthetreatmentofdegenerativediseasesYvonneS. Eisele1,2,CeciliaMonteiro1,2,ColleenFearns2,SandraE. Encalada2–4,R. LukeWiseman2,5,EvanT. Powers1andJefferyW. Kelly1,2,6Abstract
2、Theaggregationofspecificproteinsishypothesizedtounderlieseveral
3、degenerativediseases,whicharecollectivelyknownasamyloiddisorders.However,themechanisticconnectionbetweentheprocessofproteinaggregationandtissuedegenerationisnotyetfullyunderstood.Here,wereviewcurrentandemergingstrategiestoameliorateaggregation-associateddegenerativedisord
4、ers,withafocusondisease-modifyingstrategiesthatpreventtheformationofand/oreliminateproteinaggregates.Persuasivepharmacologicalandgeneticevidencenowsupportsproteinaggregationasthecauseofpostmitotictissuedysfunctionorloss.However,amoredetailedunderstandingofthefactorsthattr
5、iggerandsustainaggregateformationandofthestructure–activityrelationshipsunderlyingproteotoxicityisneededtodevelopfuturedisease-modifyingtherapies.Transthyretin(TTR)1,immunoglobulinlightchainStronggenetic,pharmacological,biochemicalandAmyloidfibrils(LC)2,serumamyloidA(SAA)
6、3andamyloid‑β(Aβ)4pathologicalevidencesupportsthehypothesisthatLateralassembliesofproteinaggregatesadoptingaareexamplesofmorethan30humanproteinsthatseemhumanamyloiddiseasesresultfromtheprocessofcross‑β‑sheetstructure.tocausearangeofdegenerativedisordersowingtotheirprotein
7、aggregation,oramyloidogenesis21–28(FIG. 1).Theseaggregatesbindtomisfoldingand/ormisassemblyintovariousaggregateItisimportanttorecognizethatthereisanincom‑Congored,thioflavinTstructures5.Theseamyloiddiseasesarenamedafterpleteunderstandingofaggregation,bothin vitroandandana
8、logousaromatics.theirpathologicalhallmarks:cross‑β‑sheetaggregates,inmulticellularorganisms,becauseprobestomonitororamyloidfibrils6,7.Amyloidfibrilsinaspecificdiseasethedifferenttypesofaggregatesformedorstructuresaregenerallycomposedpredominantlyofoneprotein5.yieldeddurin
9、gthisdynamicprocessarenotavailable.AmyloidfibrilsfromdifferentdiseasesandcomposedIntheabsenceofm
