Expression of human amyloid precursor protein in the skeletal muscles of Drosophila results in age- and activity-dependent muscle weakness.docVIP

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Expression of human amyloid precursor protein in the skeletal muscles of Drosophila results in age- and activity-dependent muscle weakness.doc

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Expression of human amyloid precursor protein in the skeletal muscles of Drosophila results in age- and activity-dependent muscle weakness

Kimetal.BMCPhysiology2011,11:7 /1472-6793/11/7 RESEARCH ARTICLE OpenAccess Expressionofhumanamyloidprecursorprotein intheskeletalmusclesofDrosophilaresultsin age-andactivity-dependentmuscleweakness ChulKim1,SapeckshitaSrivastava2,MarianRice3,TanjaAGodenschwege4,BrookeBentley5,SaranyaRavi3, ShuangShao3,CraigTWoodard3andLawrenceMSchwartz1,2,5* Abstract Background:OneofthehallmarksofAlzheimer’sdisease,andseveralotherdegenerativedisorderssuchas InclusionBodyMyositis,istheabnormalaccumulationofamyloidprecursorprotein(APP)anditsproteolytic amyloidpeptides.TobetterunderstandthepathologicalconsequencesofinappropriateAPPexpressionon developingtissues,wegeneratedtransgenicfliesthatexpresswild-typehumanAPPintheskeletalmuscles,and thenperformedanatomical,electrophysiological,andbehavioralanalysisoftheadults. Results:Weobservedthatneithermuscledevelopmentnoranimallongevitywascompromisedinthese transgenicanimals.However,humanAPPexpressingadultsdevelopedage-dependentdefectsinbothclimbing andflying.Wecouldadvanceorretardtheonsetofsymptomsbyrearinganimalsinvialswithdifferentsurface properties,suggestingthathumanAPPexpression-mediatedbehavioraldefectsareinfluencedbymuscleactivity. Musclesfromtransgenicanimalsdidnotdisplayproteinaggregatesorstructuralabnormalitiesatthelightor transmissionelectronmicroscopiclevels.Inagreementwithgeneticstudiesperformedwithdeveloping mammalianmyoblasts,weobservedthatco-expressionoftheubiquitinE3ligaseParkincouldamelioratehuman APP-induceddefects. Conclusions:Thesedatasuggestthat:1)ectopicexpressionofhumanAPPinfruitfliesleadstoage-andactivity- dependentbehavioraldefectswithoutovertchangestomuscledevelopmentorstructure;2)environmental influencescangreatlyalterthephenotypicconsequencesofhumanAPPtoxicity;and3)geneticmodifiersofAPP- inducedpathologycanbeidentifiedandanalyzedinthismodel. Keywords:amyloidprecursorprotein(APP)Drosophila,muscle,mitochondria,electronmicroscopy,apoptosis, Parkin Background APPbecamethesubjectofintenseinvestigationwhen Amyloidpr