title: Prion protein (PrP) knock-out mice show altered iron metabolism: a functional role for PrP in iron uptake and transport.
abstract: Despite overwhelming evidence implicating the prion protein (PrP) in prion disease pathogenesis, the normal function of this cell surface glycoprotein remains unclear. In previous reports we demonstrated that PrP mediates cellular iron uptake and transport, and aggregation of PrP to the disease causing PrP-scrapie (PrP(Sc)) form results in imbalance of iron homeostasis in prion disease affected human and animal brains. Here, we show that selective deletion of PrP in transgenic mice (PrP(KO)) alters systemic iron homeostasis as reflected in hematological parameters and levels of total iron and iron regulatory proteins in the plasma, liver, spleen, and brain of PrP(KO) mice relative to matched wild type controls. Introduction of radiolabeled iron ((59)FeCl(3)) to Wt and PrP(KO) mice by gastric gavage reveals inefficient transport of (59)Fe from the duodenum to the blood stream, an early abortive spike of erythropoiesis in the long bones and spleen, and eventual decreased (59)Fe content in red blood cells and all major organs of PrP(KO) mice relative to Wt controls. The iron deficient phenotype of PrP(KO) mice is reversed by expressing Wt PrP in the PrP(KO) background, demonstrating a functional role for PrP 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 PrP(Sc) form induces imbalance of brain iron homeostasis, resulting in disease associated neurotoxicity.
authors: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors: Ajay
authors: A
authors: Singh
authors: Qingzhong
authors: Q
authors: Kong
authors: Xiu
authors: X
authors: Luo
authors: Robert B
authors: RB
authors: Petersen
authors: Howard
authors: H
authors: Meyerson
authors: Neena
authors: N
authors: Singh
mesh_terms: D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism
chemical_list: D018620:PrPSc Proteins; D007501:Iron