Role of glycosylphosphatidylinositols in the activation of phospholipase A2 and the neurotoxicity of prions.

Abstract

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 (PrP(c)) or from disease-associated isoforms (PrP(Sc)), 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 PrP(Sc) species found in Gerstmann-Straussler-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.

• Authors: Clive Bate, Alun Williams
• Journal: The Journal of general virology (J Gen Virol) Vol. 85 Issue Pt 12 Pg. 3797-3804 (Dec 2004) ISSN: 0022-1317 [Print] England
• PMID: 15557253 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Caspase Inhibitors
• Glycosylphosphatidylinositols
• Prions
• Phospholipases A
• Phospholipases A2
• Casp3 protein, mouse
• Caspase 3
• Dinoprostone

Topics

• Animals
• Apoptosis
• Caspase 3
• Caspase Inhibitors
• Cell Line, Tumor
• Dinoprostone (biosynthesis)
• Enzyme Activation
• Glycosylphosphatidylinositols (physiology)
• Mice
• Microglia (physiology)
• Nerve Degeneration
• Neurons (pathology)
• Phospholipases A (metabolism)
• Phospholipases A2
• Prions (toxicity)