The PrPC [cellular isoform of PrP (prion protein)] can undergo a conformational conversion to produce a proteinase-resistant form PrPSc (scrapie isoform of PrP), a step critical for the development of prion disease. Although essential for disease progression, the normal cellular function of PrPC remains unknown. Suggestions to date have centred on a protective role against oxidative stress. We have demonstrated that ROS (reactive oxygen species)-mediated β-cleavage of PrPC occurs at the cell surface, can be inhibited following hydroxyl radical quenching and has a prerequisite for the octarepeat region in the N-terminus of the protein. Significantly, two disease-associated mutants of PrP, namely PG14 and A116V (Ala116→Val), were unable to undergo β-cleavage and this lack of proteolysis was accompanied by functional consequences in cells expressing these mutant proteins. The cells were found to be less viable following exposure to copper and H2O2, had reduced levels of glutathione peroxidase and increased amounts of intracellular oxygen radicals. These results suggest that β-cleavage of PrPC is an initial consequence following exposure to ROS in the extracellular environment contributing to a pathway involved in antioxidant protection of neuronal cells.
Reactive oxygen species (ROS)-mediated β-cleavage of the prion protein in the mechanism of the cellular response to oxidative stress
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N.T. Watt, N.M. Hooper; Reactive oxygen species (ROS)-mediated β-cleavage of the prion protein in the mechanism of the cellular response to oxidative stress. Biochem Soc Trans 26 October 2005; 33 (5): 1123–1125. doi: https://doi.org/10.1042/BST0331123
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