Role of glycosylphosphatidylinositols in the activation of phospholipase A(2) and the neurotoxicity of prions

Bate, C. and Williams, A. (2004) Role of glycosylphosphatidylinositols in the activation of phospholipase A(2) and the neurotoxicity of prions. Journal of General Virology, 85, pp. 3797-3804. (doi: 10.1099/vir.0.80366-0)

Abstract

Prion-induced neuronal injury in vivo is associated with prostaglandin E2 production, a process that can be reproduced in tissue-culture models of prion disease. In the present study, neuronal phospholipase A2 was activated by glycosylphosphatidylinositols (GPIs) isolated from the cellular prion protein (PrPc) or from disease-associated isoforms (PrPSc), resulting in prostaglandin E2 production, but not by GPIs isolated from Thy-1. The ability of GPIs to activate neuronal phospholipase A2 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 E2 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 A2 activation by PrP-GPIs as an early event in prion-induced neurodegeneration.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: UNSPECIFIED
• Authors: Bate, C., and Williams, A.
• College/School: College of Medical Veterinary and Life Sciences
• Journal Name: Journal of General Virology
• Publisher: Society for General Microbiology
• ISSN: 0022-1317
• ISSN (Online): 1465-2099