DYT1 Knock-In Mice Are Not Sensitized against Mitochondrial Complex-II Inhibition 英文参考文献.docVIP

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DYT1 Knock-In Mice Are Not Sensitized against Mitochondrial Complex-II Inhibition 英文参考文献.doc

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DYT1 Knock-In Mice Are Not Sensitized against Mitochondrial Complex-II Inhibition 英文参考文献

DYT1Knock-InMiceAreNotSensitizedagainst MitochondrialComplex-IIInhibition NicoleBode1,CoryMassey2,PedroGonzalez-Alegre1,2* 1DepartmentofNeurology,RoyJandLucilleCarverCollegeofMedicineattheUniversityofIowa,IowaCity,Iowa,UnitedStatesofAmerica, 2GraduateProgramin Neuroscience,theUniversityofIowa,IowaCity,Iowa,UnitedStatesofAmerica Abstract DYT1iscausedbyapartlypenetrantdominantmutationinTOR1Athatleadstoaglutamicaciddeletion(DE)intorsinA. Identifying environmental factors that modulate disease pathogenesis and penetrance could help design therapeutic strategies for dystonia. Several cell-based studies suggest that expression of torsinA(DE) increases the susceptibility of neuronal cells to challenges to their oxidative/energy metabolism. Based on those reports, we hypothesized that mice expressingtorsinA(DE)wouldbemoresusceptiblethancontrollittermatestotheeffectsofoxidativestressandATPdeficits caused by disruption of the mitochondrial respiratory chain in neurons. To test this hypothesis, we administered 20 or 50mg/kg/dayoftheirreversiblecomplex-IIinhibitor3-nitropropionicacid(3-NP)intraperitoneallyfor15consecutivedays to young heterozygote DYT1 knock-in (KI) mice and wild type littermates. Repeated phenotypic assessments were performedatbaseline,duringandaftertheinjections.Animalswerethensacrificedandtheirbrainsprocessedforprotein analysis.Theadministrationof20mg/kg3-NPledtoincreasedlevelsoftorsinAinthestriatum,themaintargetof3-NP,but didnotcausemotordysfunctioninDYT1KIorcontrolmice.Theadministrationof50mg/kg/dayof3-NPcausedthedeath of ,40% of wild type animals. Interestingly, DYT1 KI animals showed significantly reduced mortality. Surviving animals exhibited abnormal motor behavior during and right after the injection period, but recovered by 4 weeks postinjection independentofgenotype.Incontrasttothefindingsreportedinculturedcells,thesestudiessuggesttheDYT1mutation doesnotsensitizecentralneuronsagainstthetoxiceffectsofoxidativestressandenergydeficits. C