The effect of Fenton reaction on protease-resistant prion protein (PrPSc) degradation and scrapie infectivity

In prion diseases, metal imbalances in brain and/or metal substitutions for copper in prion protein suggest that metal-catalyzed oxidation (MCO) and oxidative stress may affect cellular function and accumulation of protease-resistant prion protein (PrPSc). We examined the effect of metal-induced oxidative stress by Fenton reaction on prion protein with regard to its degradation, insolubility, and infectivity. Precipitation and insolubility of prion protein were induced by Fenton reaction in scrapie-infected brain homogenate. Results showed an increase in hydroxylation products (thiobarbituric acid reactive substances; TBARS) and a decrease of ferrous ion (Fe2+) levels after Fenton reaction. Efficiency of metal-induced oxidation was higher for Fe2+ than Mn2+. Compared to untreated samples, there was increased susceptibility to proteolytic degradation of PrPSc after treatment with 3.12–12.5 mM Fe2+–Mn2+/H2O2. Interestingly, we observed that Fenton reaction could extend incubation periods, indicating a decrease in scrapie infectivity. These results suggest that PrPSc hydroxylation and degradation may affect PrP conversion and the pathogenesis of prion diseases.