Perturbation with Intrabodies Reveals That Calpain Cleavage Is Required for Degradation of Huntingtin Exon 1 英文参考文献.docVIP

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Perturbation with Intrabodies Reveals That Calpain Cleavage Is Required for Degradation of Huntingtin Exon 1 英文参考文献.doc

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Perturbation with Intrabodies Reveals That Calpain Cleavage Is Required for Degradation of Huntingtin Exon 1 英文参考文献

PerturbationwithIntrabodiesRevealsThatCalpain CleavageIsRequiredforDegradationofHuntingtin Exon1 AmberL.Southwell1¤a,CharlesW.Bugg1,LindaS.Kaltenbach2,DeniseDunn2,StefanieButland3, AndreasWeiss4,PaoloPaganetti4¤b,DonaldC.Lo2,PaulH.Patterson1* 1DivisionofBiology,CaliforniaInstituteofTechnology,Pasadena,California,UnitedStatesofAmerica,2CenterforDrugDiscovery,DepartmentofNeurobiology,Duke University Medical Center, Durham, North Carolina, United States of America, 3Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, UniversityofBritishColumbia,Vancouver,BritishColumbia,Canada,4NeuroscienceDiscovery,NovartisInstitutesforBioMedicalResearch,NovartisPharmaAG,Basel, Switzerland Abstract Background: Proteolytic processing of mutant huntingtin (mHtt), the protein that causes Huntington’s disease (HD), is criticalformHtttoxicityanddiseaseprogression.mHttcontainsseveralcaspaseandcalpaincleavagesitesthatgenerateN- terminalfragmentsthataremoretoxicthanfull-lengthmHtt.Furtherprocessingisthenrequiredforthedegradationof these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutictargetforHD. Methodology/PrincipalFindings:Wehaveusedintrabodies,intracellularlyexpressedantibodyfragments,togaininsight into the mechanism of mutant huntingtin exon 1 (mHDx-1) clearance. Happ1, an intrabody recognizing the proline-rich regionofmHDx-1,reducesthelevelofsolublemHDx-1byincreasingclearance.Whileproteasomeandmacroautophagy inhibitors reduce turnover of mHDx-1, Happ1 is still able to reduce mHDx-1 under these conditions, indicating Happ1- acceleratedmHDx-1clearancedoesnotrelyontheseprocesses.Incontrast,acalpaininhibitororaninhibitoroflysosomal pHblockHapp1-mediatedaccelerationofmHDx-1clearance.TheseresultssuggestthatmHDx-1iscleavedbycalpain,likely followedby lysosomal degradation andthis process regulates theturnover rate ofmHDx-1. Sequenceanalysis identifies aminoacid(AA)15asapotentialcalpaincl