Reduction of Protein Translation and Activation of Autophagy Protect against PINK1 Pathogenesis in Drosophila melanogaster 英文参考文献.docVIP

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Reduction of Protein Translation and Activation of Autophagy Protect against PINK1 Pathogenesis in Drosophila melanogaster 英文参考文献.doc

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Reduction of Protein Translation and Activation of Autophagy Protect against PINK1 Pathogenesis in Drosophila melanogaster 英文参考文献

ReductionofProteinTranslationandActivationof AutophagyProtectagainstPINK1Pathogenesisin Drosophilamelanogaster SongLiu,BingweiLu* DepartmentofPathology,StanfordUniversitySchoolofMedicine,Stanford,California,UnitedStatesofAmerica Abstract MutationsinPINK1andParkincausefamilial,earlyonsetParkinson’sdisease.InDrosophilamelanogaster,PINK1andParkin mutantsshowsimilarphenotypes,suchasswollenanddysfunctionalmitochondria,muscledegeneration,energydepletion, and dopaminergic (DA) neuron loss. We previously showed that PINK1 and Parkin genetically interact with the mitochondrialfusion/fissionpathway,andPINK1andParkinwererecentlyproposedtoformamitochondrialqualitycontrol system that involves mitophagy. However, the in vivo relationships among PINK1/Parkin function, mitochondrial fission/ fusion,andautophagyremainunclear;andothercellulareventscriticalforPINK1pathogenesisremaintobeidentified.Here we show that PINK1 genetically interacted with the protein translation pathway. Enhanced translation through S6K activation significantly exacerbated PINK1 mutant phenotypes, whereas reduction of translation showed suppression. InductionofautophagybyAtg1overexpressionalsorescuedPINK1mutantphenotypes,eveninthepresenceofactivated S6K.DownregulationoftranslationandactivationofautophagywerealreadymanifestedinPINK1mutant,suggestingthat they represent compensatory cellular responses to mitochondrial dysfunction caused by PINK1 inactivation, presumably servingtoconserveenergy.Interestingly,theenhancedPINK1mutantphenotypeinthepresenceofactivatedS6Kcouldbe fullyrescuedbyParkin,apparentlyinanautophagy-independentmanner.Ourresultsrevealcomplexcellularresponsesto PINK1inactivationandsuggestnoveltherapeuticstrategiesthroughmanipulationofthecompensatoryresponses. Citation:LiuS,LuB(2010)ReductionofProteinTranslationandActivationofAutophagyProtectagainstPINK1PathogenesisinDrosophilamelanogaster .PLoS Genet6(12):e1001237.doi:10.1371/journal.pgen.1001237 Editor:HarryT.Orr,UniversityofMinnesota,UnitedSt