PNAS：建立腓骨肌萎缩症模式生物

先前的研究发现，腓骨肌萎缩症患者多伴有YARS基因变异。YARS基因是体内合成蛋白质的一种重要酶的编码基因。最新的研究首次将YARS基因与腓骨肌萎缩症联系在一起。研究人员设计将四种不同的YARS变异基因导入果蝇，导入正常YARS基因的果蝇没有出现任何疾病症状，携带变异YARS基因的果蝇均表现出腓骨肌萎缩症症状，如运动能力下降，神经末梢变性。（生物谷Bioon.com）生物谷推荐原始出处：PNASJune26,2009,doi:10.1073/pnas.0905339106Dominantmutationsinthetyrosyl-tRNAsynthetasegenerecapitulateinDrosophilafeaturesofhumanCharcotCMarieCToothneuropathyErikStorkebauma,b,1,RicardoLeit?o-Gon?alvesa,b,c,d,1,TanjaGodenschwegee,LeslieNanglef,g,MonicaMejiae,IngeBosmansa,b,TinneOomsc,d,AnJacobsc,d,PatrickVanDijckh,i,Xiang-LeiYangf,PaulSchimmelf,2,KoenNorgaa,j,VincentTimmermanc,d,PatrickCallaertsa,b,1,3andAlbenaJordanovaDominant-intermediateCharcotCMarieCToothneuropathy（DI-CMT）ischaracterizedbyaxonaldegenerationanddemyelinationofperipheralmotorandsensoryneurons.ThreedominantmutationsintheYARSgene,encodingtyrosyl-tRNAsynthetase（TyrRS）,havesofarbeenassociatedwithDI-CMTtypeC.ThemolecularmechanismsthroughwhichmutationsinYARSleadtoperipheralneuropathyarecurrentlyunknown,andanimalmodelsforDI-CMTCarenotyetavailable.Here,wereportthegenerationofaDrosophilamodelofDI-CMTC:expressionofthe3mutant―butnotwildtype―TyrRSinDrosophilarecapitulatesseveralhallmarksofthehumandisease,includingaprogressivedeficitinmotorperformance,electrophysiologicalevidenceofneuronaldysfunctionandmorphologicalsignsofaxonaldegeneration.Notonlyubiquitous,butalsoneuron-specificexpressionofmutantTyrRS,inducesthesephenotypes,indicatingthatthemutantenzymehascell-autonomouseffectsinneurons.Furthermore,biochemicalandgeneticcomplementationexperimentsrevealedthatlossofenzymaticactivityisnotacommonfeatureofDI-CMTC-associatedmutations.Thus,theDI-CMTCphenotypeisnotduetohaploinsufficiencyofaminoacylationactivity,butmostlikelytoagain-of-functionalterationofthemutantTyrRSorinterferencewithanunknownfunctionoftheWTprotein.OurresultsalsosuggestthatthemolecularpathwaysleadingtomutantTyrRS-associatedneurodegenerationareconservedfromfliestohumans.

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