NR ARFM
AU Bate,C.; Williams,A.
TI Role of glycosylphosphatidylinositols in the activation of phospholipase A2 and the neurotoxicity of prions
QU Journal of General Virology 2004 Dec; 85(12): 3797-804
IA http://vir.sgmjournals.org/cgi/content/full/85/12/3797
PT journal article
AB Prion-induced neuronal injury in vivo is associated with prostaglandin E(2) production, a process that can be reproduced in tissue-culture models of prion disease. In the present study, neuronal phospholipase A(2) was activated by glycosylphosphatidylinositols (GPIs) isolated from the cellular prion protein (PrPc) or from disease-associated isoforms (PrPsc), resulting in prostaglandin E(2) production, but not by GPIs isolated from Thy-1. The ability of GPIs to activate neuronal phospholipase A(2) was lost following the removal of acyl chains or cleavage of the phosphatidylinositol-glycan linkage, and was inhibited by a mAb that recognized phosphatidylinositol. In competition assays, pretreatment of neurons with partial GPIs, inositol monophosphate or sialic acid reduced the production of prostaglandin E(2) in response to a synthetic miniprion (sPrP106), a synthetic correlate of a PrPsc species found in Gerstmann-Sträussler-Scheinker disease (HuPrP82-146), prion preparations or high concentrations of PrP-GPIs. In addition, neurons treated with inositol monophosphate or sialic acid were resistant to the otherwise toxic effects of sPrP106, HuPrP82-146 or prion preparations. This protective effect was selective, as inositol monophosphate- or sialic acid-treated neurons remained susceptible to the toxicity of arachidonic acid or platelet-activating factor. Addition of PrP-GPIs to cortical neuronal cultures increased caspase-3 activity, a marker of apoptosis that is elevated in prion diseases. In contrast, treatment of such cultures with inositol monophosphate or sialic acid greatly reduced sPrP106-induced caspase-3 activity and, in co-cultures, reduced the killing of sPrP106-treated neurons by microglia. These results implicate phospholipase A(2) activation by PrP-GPIs as an early event in prion-induced neurodegeneration.
MH Animals; Apoptosis; Caspases/antagonists & inhibitors; Cell Line, Tumor; Dinoprostone/biosynthesis; Enzyme Activation; Glycosylphosphatidylinositols/*physiology; Mice; Microglia/physiology; Nerve Degeneration; Neurons/*pathology; Phospholipases A/*metabolism; Prions/*toxicity; Research Support, Non-U.S. Gov't
AD Department of Veterinary Pathology, Glasgow University Veterinary School, Bearsden Road, Glasgow G61 1QH, UK. c.bate@vet.gla.ac.uk
SP englisch
PO England