1887

Abstract

Prion-induced neuronal injury is associated with prostaglandin E production, a process that can be reproduced in tissue-culture models of prion disease. In the present study, neuronal phospholipase A was activated by glycosylphosphatidylinositols (GPIs) isolated from the cellular prion protein (PrP) or from disease-associated isoforms (PrP), resulting in prostaglandin E production, but not by GPIs isolated from Thy-1. The ability of GPIs to activate neuronal phospholipase A 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 in response to a synthetic miniprion (sPrP106), a synthetic correlate of a PrP 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 activation by PrP-GPIs as an early event in prion-induced neurodegeneration.

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2004-12-01
2020-10-29
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