Optimised and Rapid Pre-clinical Screening in the SOD1G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis (ALS) 英文参考文献.docVIP

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Optimised and Rapid Pre-clinical Screening in the SOD1G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis (ALS) 英文参考文献.doc

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Optimised and Rapid Pre-clinical Screening in the SOD1G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis (ALS) 英文参考文献

OptimisedandRapidPre-clinicalScreeninginthe SOD1G93A TransgenicMouseModelofAmyotrophic LateralSclerosis(ALS) RichardJ.Mead1,EllenJ.Bennett1,AneurinJ.Kennerley2,PaulSharp1,5,ClaireSunyach3,4,PaulKasher1, JasonBerwick2,BrigittePettmann3,4,GuiseppeBattaglia5,MimounAzzouz1,AndrewGrierson1, PamelaJ.Shaw1* 1SheffieldInstituteforTranslationalNeuroscience,DepartmentofNeuroscience,SchoolofMedicineandBiomedicalSciences,UniversityofSheffield,Sheffield,United Kingdom, 2Department of Psychology, Faculty of Science, University of Sheffield, Sheffield, United Kingdom, 3Inserm-Avenir Team, Mediterranean Institute of Neurobiology,Inmed,Marseille,France,4Faculte′ desSciences,AixMarseilleUniversite′,Marseille,France,5DepartmentofBiomedicalSciences,UniversityofSheffield, Sheffield,UnitedKingdom Abstract ThehumanSOD1G93Atransgenicmousehasbeenusedextensivelysinceitsdevelopmentin1994asamodelforamyotrophic lateralsclerosis(ALS).Inthattime,agreatmanyinsightsintothetoxicityofmutantSOD1havebeengainedusingthisand othermutantSODtransgenicmousemodels.Theyalldemonstrateaselectivetoxicitytowardsmotorneuronsandinsome casesfeaturesofthepathologyseeninthehumandisease.Thesemodelshavetwomajordrawbacks.Firstlythegenerationof robustpreclinicaldatainthesemodelshasbeenhighlightedasanareaforconcern.Secondly,theamountoftimerequiredfor a single preclinicalexperiment in these models (3–4 months) is a hurdle tothe developmentof newtherapies. We have developedaninbredC57BL/6mouselinefromtheoriginalmixedbackground(SJLxC57BL/6)SOD1G93Atransgeniclineand showherethatthediseasecourseisremarkablyconsistentandmuchlesspronetobackgroundnoise,enablingreduced numbersofmicefortestingoftherapeutics.Secondlywehaveidentifiedveryearlyreadoutsshowingalargedeclineinmotor function compared to normal mice. This loss of motor function has allowed us to develop an early, sensitive and rapid screening protocol for the initial phases of denervation of muscle fibers, observed in this model. We describe multiple, quantitativereadouts