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Converging evidence leaves little doubt that a change in the conformation of prion protein (PrP C ) from a mainly α-helical to a β-sheet rich PrP-scrapie (PrP Sc ) form is the main event responsible for prion disease associated neurotoxicity. However, neither the mechanism of toxicity by PrP Sc , nor the normal function of PrP C  is entirely clear. Recent reports suggest that imbalance of iron homeostasis is a common feature of prion infected cells and mouse models, implicating redox-iron in prion disease pathogenesis. In this report, we provide evidence that PrP C  mediates cellular iron uptake and transport, and mutant PrP forms alter cellular iron levels differentially. Using human neuroblastoma cells as models, we demonstrate that over-expression of PrP C  increases intra-cellular iron relative to non-transfected controls as indicated by an increase in total cellular iron, the cellular labile iron pool (LIP), and iron content of ferritin. As a result, the levels of iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) are decreased, and expression of iron storage protein ferritin is increased. The positive effect of PrP C  on ferritin iron content is enhanced by stimulating PrP C  endocytosis, and reversed by cross-linking PrP C  on the plasma membrane. Expression of mutant PrP forms lacking the octapeptide-repeats, the membrane anchor, or carrying the pathogenic mutation PrP 102L  decreases ferritin iron content significantly relative to PrP C  expressing cells, but the effect on cellular LIP and levels of Tf, TfR, and ferritin is complex, varying with the mutation. Neither PrP C  nor the mutant PrP forms influence the rate or amount of iron released into the medium, suggesting a functional role for PrP C  in cellular iron uptake and transport to ferritin, and dysfunction of PrP C  as a significant contributing factor of brain iron imbalance in prion disorders.

Prion Protein Modulates Cellular Iron Uptake: A Novel Function with Implications for Prion Disease Pathogenesis