Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

Physiological role of PrP in anti-oxidant defence

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 subject to endoproteolysis at the end of the copper-binding octapeptide repeats through the action of reactive oxygen species (ROS); a process termed beta-cleavage. PrPC stably expressed in human neuroblastoma SH-SY5Y cells is subject to beta-cleavage upon exposure of the cells to hydrogen peroxide and Cu2+. ROS-mediated beta-cleavage of cell-surface PrPC occurred within minutes and was inhibited by the hydroxyl radical quencher dimethyl sulphoxide. This ROS-mediated beta-cleavage was not blocked by inhibitors of calpains and the resulting C-terminal fragment (C2) was sensitive to digestion by proteinase K. A construct of PrP lacking the octapeptide repeats, PrPDeltaoct, failed to undergo ROS-mediated beta-cleavage, as did two mutant forms of PrP, PG14 and A116V, associated with human prion diseases. Cells expressing PrPDeltaoct, PG14 or A116V had reduced viability and glutathione peroxidase activity and increased intracellular free radicals as compared to cells expressing wild type PrP when challenged with H2O2 and Cu2+. Thus lack of ROS-mediated beta-cleavage of PrP correlated with the sensitivity of the cells to oxidative stress. These data suggest that the beta-cleavage of PrPC may be an early event in the mechanism by which PrP protects cells against oxidative stress.

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Nigel M. HOOPER, (Chair of Biochemistry)
Tel.: +44-113-2333163
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