Stress and muscular dystrophy: A genetic screen for Dystroglycan and Dystrophin interactors in Drosophila identifies cellular stress response components

摘要

InDrosophila,likeinhumans,DystrophinGlycoproteinComplex(DGC)deficienciescausealifespanshorteningdisease,associatedwithmuscledysfunction.Weperformedthefirstinvivogeneticinteractionscreeninageingdystrophicmusclesandidentifiedgenesthathavenotbeenshownbeforetohavearoleinthedevelopmentofmusculardystrophyandinteractwithdystrophinand/ordystroglycan.Mutationsinmanyofthefoundinteractinggenescauseage-dependentmorphologicalandheat-inducedphysiologicaldefectsinmuscles,suggestingtheirimportanceinthetissue.Majorityofthemisphylogeneticallyconservedandimplicatedinhumandisorders,mainlytumorsandmyopathies.Functionallytheycanbedividedintothreemaincategories:proteinsinvolvedincommunicationbetweenmuscleandneuron,andinterestingly,inmechanicalandcellularstressresponsepathways.Ourdatashowthatstressinducesmuscledegenerationandacceleratesage-dependentmusculardystrophy.Dystrophicmusclesarealreadycompromised;andasaconsequencetheyarelessadaptiveandmoresensitivetoenergeticstressandtochangesintheambienttemperature.However,onlydystroglycan,butnotdystrophindeficiencycausesextrememyodegenerationinducedbyenergeticstresssuggestingthatdystroglycanmightbeacomponentofthelow-energypathwayandactasatransducerofenergeticstressinnormalanddystrophicmuscles./p/div