Prion Protein (PrP) Knock-Out Mice Show Altered Iron Metabolism A Functional Role for PrP in Iron Uptake and Transport 英文参考文献.docVIP

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Prion Protein (PrP) Knock-Out Mice Show Altered Iron Metabolism A Functional Role for PrP in Iron Uptake and Transport 英文参考文献.doc

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Prion Protein (PrP) Knock-Out Mice Show Altered Iron Metabolism A Functional Role for PrP in Iron Uptake and Transport 英文参考文献

PrionProtein(PrP)Knock-OutMiceShowAlteredIron Metabolism:AFunctionalRoleforPrPinIronUptakeand Transport AjaySingh,QingzhongKong,XiuLuo,RobertB.Petersen,HowardMeyerson,NeenaSingh* DepartmentofPathology,CaseWesternReserveUniversity,Cleveland,Ohio,UnitedStatesofAmerica Abstract Despiteoverwhelmingevidenceimplicatingtheprionprotein(PrP)inpriondiseasepathogenesis,thenormalfunctionof thiscellsurfaceglycoproteinremainsunclear.InpreviousreportswedemonstratedthatPrPmediatescellularironuptake and transport, and aggregation of PrP to the disease causing PrP-scrapie (PrPSc) form results in imbalance of iron homeostasisinpriondiseaseaffectedhumanandanimalbrains.Here,weshowthatselectivedeletionofPrPintransgenic mice (PrPKO) alters systemic iron homeostasis as reflected in hematological parameters and levels of total iron and iron regulatoryproteinsintheplasma,liver,spleen,andbrainofPrPKOmicerelativetomatchedwildtypecontrols.Introduction of radiolabeled iron (59FeCl3) to Wt and PrPKO mice by gastric gavage reveals inefficient transport of 59Fe from the duodenum to the blood stream, an early abortive spike of erythropoiesis in the long bones and spleen, and eventual decreased 59Fe content in red blood cells and all major organs of PrPKO mice relative to Wt controls. The iron deficient phenotypeofPrPKOmiceisreversedbyexpressingWtPrPinthePrPKObackground,demonstratingafunctionalroleforPrP in iron uptake and transport. Since iron is required for essential metabolic processes and is also potentially toxic if mismanaged, these results suggest that loss of normal function of PrP due to aggregation to the PrPSc form induces imbalanceofbrainironhomeostasis,resultingindiseaseassociatedneurotoxicity. Citation:SinghA,KongQ,LuoX,PetersenRB,MeyersonH,etal.(2009)PrionProtein(PrP)Knock-OutMiceShowAlteredIronMetabolism:AFunctionalRolefor PrPinIronUptakeandTransport.PLoSONE4(7):e6115.doi:10.1371/journal.pone.0006115 Editor:JosephElKhoury,MassachusettsGeneralHospitalandHarvardMedicalSchool,UnitedSt