Prion Protein Regulates Iron Transport by Functioning as a Ferrireductase

Prion protein (PrP^C) is implicated in the pathogenesis of prion disorders, but its normal function is unclear. We demonstrate that PrP^C is a ferrireductase (FR), and its absence causes systemic iron deficiency in PrP knock-out mice (PrP^-/-). When exposed to non-transferrin-bound (NTB) radioactive-iron (⁵⁹FeCl₃) by gastric-gavage, PrP^-/- mice absorb significantly more ⁵⁹Fe from the intestinal lumen relative to controls, indicating appropriate systemic response to the iron deficiency. Chronic exposure to excess dietary iron corrects this deficiency, but unlike wild-type (PrP^+/+) controls that remain iron over-loaded, PrP^-/- mice revert back to the iron deficient phenotype after 5 months of chase on normal diet. Bone marrow (BM) preparations of PrP^-/- mice on normal diet show relatively less stainable iron, and this phenotype is only partially corrected by intraperitoneal administration of excess iron-dextran. Cultured PrP^-/- BM-macrophages incorporate significantly less NTB-⁵⁹Fe in the absence or presence of excess extracellular iron, indicating reduced uptake and/or storage of available iron in the absence of PrP^C. When expressed in neuroblastoma cells, PrP^C exhibits NAD(P)H-dependent cell-surface and intracellular FR activity that requires the copper-binding octa-peptide-repeat region and linkage to the plasma membrane for optimal function. Incorporation of NTB-⁵⁹Fe by neuroblastoma cells correlates with FR activity of PrP^C, implicating PrP^C in cellular iron uptake and metabolism. These observations explain the correlation between PrP^C expression and cellular iron levels, and the cause of iron imbalance in sporadic-Creutzfeldt-Jakob-disease brains where PrP^C accumulates as insoluble aggregates.