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1、Sidhu,AnitaDESIPRAMINEMODULATIONOFa-,g-SYNUCLEIN,ANDTHENOREPINEPHRINETRANSPORTERINANANIMALMODELOFDEPRESSIONRunningTitle:a-andg-SynucleinmodulationbydesipramineindepressionAlexisM.Jeannotte,Ph.D.1,2,JohnG.McCarthy,B.A.1,EvaE.Redei,Ph.D.3,andAnitaSidhu,Ph.D
2、.1,2*1DepartmentofBiochemistryandMolecularandCellBiology,2InterdisciplinaryPrograminNeuroscience,GeorgetownUniversityMedicalCenter;InterdisciplinaryPrograminNeuroscience,GeorgetownUniversity,Washington,D.C.,3DepartmentofPsychiatryandBehavioralSciences,Nor
3、thwesternUniversity,Chicago,IL.*Addresscorrespondenceto:AnitaSidhu,PhD,Head,LaboratoryofMolecularNeurochemistry;TheResearchBuilding,RoomW222;3970ReservoirRoad,NW,Washington,D.C.20007;Tel:202-687-0273;Fax:202-687-0279;E-mail:sidhua@georgetown.eduKeyWords:a
4、-synuclein;g-synuclein;desipramine;microtubule;Parkinson’sdisease;depression.1Abbreviations:a-synuclein,a-Syn;g-synuclein,g-Syn;A/Gproteinagarosebeads,Bds;cytochalasinD,CD;desipramine,DMI;immunoprecipitation,IP;microtubule,MT;monoclonalantibody,mAb;Norepi
5、nephrinetransporter,NET;norepinephrine,NE;non-immuneserum,NI;polyclonalantibody,pAb;Serotonintransporter,SERT;Sprague-Dawley,SD;Wistar-Kyoto,WKY;Wistar,Wis.47Sidhu,AnitaABSTRACTThemechanismsunderlyingdepressionremainelusive.Wepreviouslydeterminedthatα-Syn
6、uclein(a-Syn)modulatestheactivityandtraffickingofthenorepinephrinetransporter(NET)inamannerthatisdependentonitsinteractionswithmicrotubules(MTs).Herewesoughttodetermineifa-Syn,ortheothersynucleinfamilymembers,b-synuclein(b-Syn)andg-synuclein(g-Syn),modula
7、teNETactivityinananimalmodelofdepression,theWistar-Kyoto(WKY)rat.TheNET-selectiveantidepressantdesipramine(DMI)waschronicallyadministeredfor14daystoWKYratsandthestrainfromwhichitwasoutbredthatdoesnotshowdepressive-likebehavior,theWistarrat.Thisdrugregimen
8、inducedsignificantbehavioralimprovementsintheWKY,butnottheWistarrat,intheforcedswimtest.InWKYratstherewasanoverexpressionofγ-SynwhichwasreducedfollowingDMItreatment.Inparallel,DMIcausedanincreaseinbotha-SynandNETint
