Prion metal interaction: is prion pathogenesis a cause or a consequence of metal imbalance?

Functional role of cellular prion protein (PrPc) has been hypothesized to be in metal homeostasis and providing cells with a superoxide dismutase (SOD)-like activity to escape damage by reactive oxygen species (ROS). PrPc interacts with a range of divalent metal ions and undergoes Cu2+ as well as Zn2+-associated endocytosis, thereby maintaining homeostasis of these and other metal ions. Conformational change to a beta-sheet rich, protease resistant entity, reminiscent of the disease-associated scrapie form called PrPsc, has been found to be induced by interaction of PrPc with metal ions like Cu2+, Zn2+, Mn2+ and Fe2+. This review compiles data from various experimental studies of the interaction of metals with PrPc. The effect of metal ions on the expression and conformation of the prion protein is described in detail with emphasis on their possible physiological and pathogenic role. Further, a hypothesis is presented where attainment of altered conformation by metal-bound PrPc has been viewed as a deleterious consequence of efforts made by cells to maintain metal homeostasis. Thus, PrPc presumably sacrifices itself by converting into PrPsc form in an attempt to protect cells from the toxicity of metal imbalance. Finally, possible reasons for contradictions reported in the literature on the subject are explored and experimental approaches to resolve the same are suggested.