NR ATHH
AU Watt,N.T.; Taylor,D.R.; Hooper,N.M.
TI Reactive Oxygen Species (ROS) -Mediated Beta-Cleavage of the Prion Protein in the Mechanism of the Cellular Response to Oxidative Stress
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Cell Biology of PrPc and PrPsc CELL-13
PT Konferenz-Poster
AB The cellular prion protein (PrPc) is critical for the development of prion diseases. However, the physiological role of PrPc is less clear, although a role in the cellular resistance to oxidative stress has been proposed. PrPc is cleaved at the end of the copper-binding octapeptide repeats through the action of reactive oxygen species (ROS); a process termed ß-cleavage. Here we show that ROS-mediated ß-cleavage of cell-surface PrPc occurs within minutes and was inhibited by the hydroxyl radical quencher dimethyl sulphoxide and by an antibody against the octapeptide repeats. A construct of PrP lacking the octapeptide repeats, PrPdelta-oct, failed to undergo ROS-mediated ß-cleavage, as did two mutant forms of PrP, PG14 and A116V, associated with human prion diseases. As compared to cells expressing wild type PrP, when challenged with H2O2 and Cu2+ cells expressing PrPdelta-oct, PG14 or A116V had reduced viability and glutathione peroxidase activity and increased intracellular free radicals. Thus lack of ROS-mediated ß-cleavage of PrP correlated with the sensitivity of the cells to oxidative stress. These data indicate that the ß-cleavage of PrPc is an early and critical event in the mechanism by which PrP protects cells against oxidative stress.
AD Nicole T. Watt, David R. Taylor, Nigel M. Hooper, University of Leeds, Leeds UK
SP englisch
PO Deutschland