Familial CJD Associated PrP Mutants within Transmembrane Region Induced Ctm-PrP Retention in ER and Triggered Apoptosis by ER Stress in SH-SY5Y Cells 英文参考文献.docVIP

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Familial CJD Associated PrP Mutants within Transmembrane Region Induced Ctm-PrP Retention in ER and Triggered Apoptosis by ER Stress in SH-SY5Y Cells 英文参考文献.doc

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Familial CJD Associated PrP Mutants within Transmembrane Region Induced Ctm-PrP Retention in ER and Triggered Apoptosis by ER Stress in SH-SY5Y Cells 英文参考文献

FamilialCJDAssociatedPrPMutantswithin TransmembraneRegionInducedCtm-PrPRetentionin ERandTriggeredApoptosisbyERStressinSH-SY5YCells XinWang1,QiShi1,KunXu1,2,ChenGao1,CaoChen1,Xiao-LiLi1,Gui-RongWang1,ChanTian1,JunHan1, Xiao-PingDong1* 1StateKeyLaboratoryforInfectiousDiseasePreventionandControl,NationalInstituteforViralDiseaseControlandPrevention,ChineseCenterforDiseaseControland Prevention,Beijing,People’sRepublicofChina,2SchoolofMedicine,Xi’anJiao-TongUniversity,Xi’an,People’sRepublicofChina Abstract Background: Genetic prion diseases are linked to point and inserted mutations in the prion protein (PrP) gene that are presumed to favor conversion of the cellular isoform of PrP (PrPC) to the pathogenic one (PrPSc). The pathogenic mechanismsandthesubcellularsitesoftheconversionarenotcompletelyunderstood.Hereweintroduceseveral PRNP gene mutations (such as, PrP-KDEL, PrP-3AV, PrP-A117V, PrP-G114V, PrP-P102L and PrP-E200K) into the cultured cells in ordertoexplorethepathogenicmechanismoffamilialpriondisease. Methodology/Principal Findings: To address the roles of aberrant retention of PrP in endoplasmic reticulum (ER), the recombinantplasmidsexpressingfull-lengthhumanPrPtailedwithanERsignalpeptideattheCOOH-terminal(PrP-KDEL) and PrP with three amino acids exchange in transmembrane region (PrP-3AV) were constructed. In the preparations of transienttransfections,18-kDCOOH-terminalproteolyticresistantfragments(Ctm-PrP)weredetectedinthecellsexpressing PrP-KDEL and PrP-3AV. Analyses of the cell viabilities in the presences of tunicamycin and brefeldin A revealed that expressions of PrP-KDEL and PrP-3AV sensitized the transfected cells to ER stress stimuli. Western blots and RT-PCR identifiedtheclearalternationsofERstressassociatedeventsinthecellsexpressingPrP-KDELandPrP-3AVthatinducedER mediatedapoptosisbyCHOPandcapase-12apoptosispathway.Moreover,severalfamilialCJDrelatedPrPmutantswere transiently introduced into the cultured cells. Only the mutants within the trans