Converging evidence leaves little doubt that a change in the conformation of
prion protein (PrP(C)) from a mainly alpha-helical to a beta-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.