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

Ajay Singh,Qingzhong Kong,Howard Meyerson,Neena Singh,Robert B Petersen,Xiu Luo,Joseph El Khoury

doi:10.1371/journal.pone.0006115

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 (PrPSc) 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 (PrPKO) 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 PrPKO mice relative to matched wild type controls. 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 phenotype of PrPKO mice is reversed by expressing Wt PrP in the PrPKO 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 PrPSc form induces imbalance of brain iron homeostasis, resulting in disease associated neurotoxicity.

Highlights

Prion protein (PrP) is a ubiquitously expressed cell surface glycoprotein linked to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor
Using the Zurich 1 PrP knock-out (PrPKO) and matched wild type (Wt) mice expressing normal levels of PrP as experimental models, we demonstrate that PrPKO mice show a phenotype of systemic iron deficiency and altered iron homeostasis compared to Wt controls
We demonstrate that the absence of PrP induces systemic iron deficiency in PrPKO mice, a phenotype that is rescued by re-introducing PrP on the PrPKO background

Summary

Introduction

Prion protein (PrP) is a ubiquitously expressed cell surface glycoprotein linked to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor. Several important facts have emerged from these studies; PrPKO mice show altered circadian rhythm and sleep pattern, increased susceptibility to neuronal damage by oxidative stress and cerebral ischemia, neurotoxicity by expression of Doppel and N-terminally truncated PrP, increased predilection to seizures, motor and cognitive abnormalities, reduced synaptic inhibition and long term potentiation in the hippocampus, altered development of the granule cell layer, mis-regulation of the cerebellar network, and age-dependent spongiform change with reactive astrogliosis [5,6,7,8,9,10]. The multiplicity of observations attributed to the absence of PrP in the same transgenic mouse line suggests its involvement in an essential function with broad implications. Though attractive, this hypothesis has remained untested

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