Copper (II) ions potently inhibit purified PrPres amplification

The structural conversion of a host protein, PrP C , into a protease‐resistant isoform, PrPres, is the central event in the pathogenesis of infectious prion diseases. Purification of native PrP C molecules from hamster brain by either cation exchange or immobilized chelator chromatographic resins yielded preparations that supported efficient amplification of scrapie‐induced PrPres in vitro . Using these purified preparations, we determined that in vitro PrPres amplification was inhibited by CuCl 2 and ZnCl 2 at IC 50 concentrations of ∼400 n m and 10 μ m , respectively. In contrast, 100 μ m MnCl 2 did not directly inhibit PrPres amplification or block Cu 2+ ‐mediated inhibition. Additionally, the inhibition of PrPres amplification by Cu 2+ ions could be reversed by addition of either neocuproine or imidazole. Cu 2+ inhibited PrPres amplification in both the presence and absence of stimulatory polyanion molecules. These biochemical findings support the hypothesis that Cu 2+ ions might regulate the pathogenesis of prion diseases in vivo .