Sequestration of free cholesterol in cell membranes by prions correlates with cytoplasmic phospholipase A2 activation

摘要: The transmissible spongiform encephalopathies (TSEs), otherwise known as the prion diseases, occur following conversion of normal cellular protein (PrPC) to an alternatively folded isoform (PrPSc). accumulation PrPSc within brain leads neurodegeneration through unidentified mechanism. Since many neurodegenerative disorders including prion, Parkinson's and Alzheimer's diseases may be modified by cholesterol synthesis inhibitors, effects infection on balance neuronal cells were examined. We report novel observation that altered membrane composition significantly increased total levels in two cell lines (ScGT1 ScN2a cells). There was a significant correlation between concentration free ScGT1 amounts PrPSc. This increase entirely result cholesterol, reduced esters cells. These reproduced primary cortical neurons addition partially purified PrPSc, but not PrPC. Crucially, synthesis. Stimulating via mevalonate, or adding exogenous had opposite effect balance. It did affect neurons; rather, it esters. Immunoprecipitation studies have shown cytoplasmic phospholipase A2 (cPLA2) co-precipitated with Furthermore, greatly both phosphorylation cPLA2 prostaglandin E2 production. Prion infection, content cells, process could replicated stimulation presence solubilisation membranes affected their function. activation PLA2 pathway, previously implicated formation PrPSc-mediated neurotoxicity. observations suggest neuropathogenesis results from altering cholesterol-sensitive processes. they raise possibility disturbances are major triggering events diseases.