Copper-dependent generation of hydrogen peroxide from the toxic prion protein fragment PrP106-126

Oligomeric forms of many of the aggregating proteins associated with neurodegenerative diseases are toxic to cultured cells. We have shown recently that Abeta and alpha-synuclein can both induce the formation of hydroxyl radicals following incubation in solution, upon the addition of Fe(II). Thus, they appear to generate hydrogen peroxide, which is converted to hydroxyl radicals via the Fenton reaction. Here we show that the widely studied toxic peptide fragment of the prion protein, PrP106-126, has exactly the same property, but only in the presence of copper ions. Since the aggregation and toxicity of PrP106-126 have been reported to be critically dependent on copper binding, our data suggest that the published cytotoxic effects of this peptide could also be due to its ability to generate hydrogen peroxide.