Oxidative impairment in scrapie-infected mice is associated with brain metals perturbations and altered antioxidant activities

P on diseases are characterized by the conversion of the normal cellular pr ion protein (PrPC) into a pathogenic isoform (PrPSc). PrPC binds copper, ha s superoxide dismutase (SOD)-like activity in vitro, and its expression aid s in the cellular response to oxidative stress. However, the interplay betw een PrPs (PrPC, PrPSc and possibly other abnormal species), copper, anti-ox idation activity and pathogenesis of prion diseases remain unclear. In this study, we reported dramatic depression of SOD-like activity by the affinit y-pu rifted PrPs from scrapie-infected brains, and together with significan t reduction of Cu/Zn-SOD activity, correlates with significant perturbation s in the divalent metals contents. We also detected elevated levels of nitr ic oxide and superoxide in the infected brains, which could be escalating t he oxidative modification of cellular proteins, reducing gluathione peroxid ase activity and increasing the levels of lipid peroxidation markers. Taken together, our results suggest that brain metal imbalances, especially copp er, in scrapie infection is likely to affect the anti-oxidation functions o f PrP and SODs, which, together with other cellular dysfunctions, predispos e the brains to oxidative impairment and eventual degeneration. To our know ledge, this is the first study documenting a physiological connection betwe en brain metals imbalances, the anti-oxidation function of PrP, and aberrat ions in the cellular responses to oxidative stress, in scrapie infection.