Reactive Oxygen Species-mediated β-Cleavage of the Prion Protein in the Cellular Response to Oxidative Stress

• Published in: The Journal of biological chemistry 2005-10, Vol.280 (43), p.35914
• Main Authors: Nicole T. Watt, David R. Taylor, Andrew Gillott, Daniel A. Thomas, W. Sumudhu S. Perera, Nigel M. Hooper
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M507327200

The cellular prion protein (PrP C ) is critical for the development of prion diseases. However, the physiological role of PrP C is less clear, although a role in the cellular resistance to oxidative stress has been proposed. PrP C is cleaved at the end of the copper-binding octapeptide repeats through the action of reactive oxygen species (ROS), a process termed β-cleavage. Here we show that ROS-mediated β-cleavage of cell surface PrP C occurs within minutes and was inhibited by the hydroxyl radical quencher dimethyl sulfoxide and by an antibody against the octapeptide repeats. A construct of PrP lacking the octapeptide repeats, PrPΔoct, failed to undergo ROS-mediated β-cleavage, as did two mutant forms of PrP, PG14 and A116V, associated with human prion diseases. As compared with cells expressing wild type PrP, when challenged with H 2 O 2 and Cu 2+ , cells expressing PrPΔoct, PG14, or A116V had reduced viability and glutathione peroxidase activity and increased intracellular free radicals. Thus, lack of ROS-mediated β-cleavage of PrP correlated with the sensitivity of the cells to oxidative stress. These data indicate that the β-cleavage of PrP C is an early and critical event in the mechanism by which PrP protects cells against oxidative stress.