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Background  The transmissible spongiform encephalopathies (TSEs), otherwise known as the prion diseases, occur following the conversion of the normal cellular prion protein (PrP C ) to an alternatively folded isoform (PrP Sc ). The accumulation of PrP Sc  within the brain leads to neurodegeneration through an unidentified mechanism. Since many neurodegenerative disorders including prion, Parkinson's and Alzheimer's diseases may be modified by cholesterol synthesis inhibitors, the effects of prion infection on the cholesterol balance within neuronal cells were examined.    Results  We report the novel observation that prion infection altered the membrane composition and significantly increased total cholesterol levels in two neuronal cell lines (ScGT1 and ScN2a cells). There was a significant correlation between the concentration of free cholesterol in ScGT1 cells and the amounts of PrP Sc . This increase was entirely a result of increased amounts of free cholesterol, as prion infection reduced the amounts of cholesterol esters in cells. These effects were reproduced in primary cortical neurons by the addition of partially purified PrP Sc , but not by PrP C . Crucially, the effects of prion infection were not a result of increased cholesterol synthesis. Stimulating cholesterol synthesis via the addition of mevalonate, or adding exogenous cholesterol, had the opposite effect to prion infection on the cholesterol balance. It did not affect the amounts of free cholesterol within neurons; rather, it significantly increased the amounts of cholesterol esters. Immunoprecipitation studies have shown that cytoplasmic phospholipase A 2  (cPLA 2 ) co-precipitated with PrP Sc  in ScGT1 cells. Furthermore, prion infection greatly increased both the phosphorylation of cPLA 2  and prostaglandin E 2  production.    Conclusion  Prion infection, or the addition of PrP Sc , increased the free cholesterol content of cells, a process that could not be replicated by the stimulation of cholesterol synthesis. The presence of PrP Sc  increased solubilisation of free cholesterol in cell membranes and affected their function. It increased activation of the PLA 2  pathway, previously implicated in PrP Sc  formation and in PrP Sc -mediated neurotoxicity. These observations suggest that the neuropathogenesis of prion diseases results from PrP Sc  altering cholesterol-sensitive processes. Furthermore, they raise the possibility that disturbances in membrane cholesterol are major triggering events in neurodegenerative diseases.

Sequestration of free cholesterol in cell membranes by prions correlates with cytoplasmic phospholipase A2activation