Abnormal brain iron homeostasis in human and animal prion disorders.

Neurotoxicity in all prion disorders is believed to result from the accumulation of PrP-scrapie (PrP(Sc)), a beta-sheet rich isoform of a normal cell-surface glycoprotein, the prion protein (PrP(C)). Limited reports suggest imbalance of brain iron homeostasis as a significant associated cause of neurotoxicity in prion-infected cell and mouse models. However, systematic studies on the generality of this phenomenon and the underlying mechanism(s) leading to iron dyshomeostasis in diseased brains are lacking. In this report, we demonstrate that prion disease-affected human, hamster, and mouse brains show increased total and redox-active Fe (II) iron, and a paradoxical increase in major iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) at the end stage of disease. Furthermore, examination of scrapie-inoculated hamster brains at different timepoints following infection shows increased levels of Tf with time, suggesting increasing iron deficiency with disease progression. Sporadic Creutzfeldt-Jakob disease (sCJD)-affected human brains show a similar increase in total iron and a direct correlation between PrP and Tf levels, implicating PrP(Sc) as the underlying cause of iron deficiency. Increased binding of Tf to the cerebellar Purkinje cell neurons of sCJD brains further indicates upregulation of TfR and a phenotype of neuronal iron deficiency in diseased brains despite increased iron levels. The likely cause of this phenotype is sequestration of iron in brain ferritin that becomes detergent-insoluble in PrP(Sc)-infected cell lines and sCJD brain homogenates. These results suggest that sequestration of iron in PrP(Sc)-ferritin complexes induces a state of iron bio-insufficiency in prion disease-affected brains, resulting in increased uptake and a state of iron dyshomeostasis. An additional unexpected observation is the resistance of Tf to digestion by proteinase-K, providing a reliable marker for iron levels in postmortem human brains. These data implicate redox-iron in prion disease-associated neurotoxicity, a novel observation with significant implications for prion disease pathogenesis.