Prion Protein (PrP) Knock-Out Mice Show Altered Iron Metabolism: A Functional Role for PrP in Iron Uptake and Transport Export

@article{citeulike:5038179, abstract = {<p>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 (⁵⁹FeCl₃) to Wt and PrP^KO 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 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.</p>}, author = {Singh, Ajay and Kong, Qingzhong and Luo, Xiu and Petersen, Robert B. and Meyerson, Howard and Singh, Neena}, citeulike-article-id = {5038179}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pone.0006115}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19568430}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19568430}, doi = {10.1371/journal.pone.0006115}, issn = {1932-6203}, journal = {PLoS ONE}, keywords = {genetics, iron, metabolism, mouse, prion}, month = {July}, number = {7}, pages = {e6115+}, posted-at = {2009-07-02 02:15:57}, priority = {2}, publisher = {Public Library of Science}, title = {Prion Protein (PrP) Knock-Out Mice Show Altered Iron Metabolism: A Functional Role for PrP in Iron Uptake and Transport}, url = {http://dx.doi.org/10.1371/journal.pone.0006115}, volume = {4}, year = {2009} }

TY - JOUR ID - citeulike:5038179 L3 - citeulike-article-id:5038179 N2 - <p>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 (⁵⁹FeCl₃) to Wt and PrP^KO 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 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.</p> IS - 7 JF - PLoS ONE SN - 1932-6203 TI - Prion Protein (PrP) Knock-Out Mice Show Altered Iron Metabolism: A Functional Role for PrP in Iron Uptake and Transport PB - Public Library of Science VL - 4 SP - e6115 KW - genetics KW - iron KW - metabolism KW - mouse KW - prion AU - Singh, Ajay AU - Kong, Qingzhong AU - Luo, Xiu AU - Petersen, Robert AU - Meyerson, Howard AU - Singh, Neena PY - 2009/07/01/ UR - http://dx.doi.org/10.1371/journal.pone.0006115 ER -