Cleavage of the amino terminus of the prion protein by reactive oxygen species

Relatively limited information is available on the processing and function of the normal cellular prion protein, PrPC. Here it is reported for the first time that PrPC undergoes a site-specific cleavage of the octapeptide repeat region of the amino terminus on exposure to reactive oxygen species. This cleavage was both copperand pH-dependent and was retarded by the presence of other divalent metal ions. The oxidative state of the cell also decreased detection of full-length PrPC and increased detection of amino-terminally fragmented PrPC within cells. Such a post-translational modification has vast implications for PrPC, in its processing, because such cleavage could alter further proteolysis, and in the formation of the scrapie isoform of the prion protein, PrPSc, because abnormal cleavage of PrPSc occurs into the octapeptide repeat region.