Show simple item record

dc.contributor.authorBate, C
dc.contributor.authorTayebi, M
dc.contributor.authorWilliams, A
dc.date.accessioned2020-12-18T03:13:11Z
dc.date.available2020-12-18T03:13:11Z
dc.date.issued2008-02-12
dc.identifierpii: 1741-7007-6-8
dc.identifier.citationBate, C., Tayebi, M. & Williams, A. (2008). Sequestration of free cholesterol in cell membranes by prions correlates with cytoplasmic phospholipase A(2) activation. BMC BIOLOGY, 6 (1), https://doi.org/10.1186/1741-7007-6-8.
dc.identifier.issn1741-7007
dc.identifier.urihttp://hdl.handle.net/11343/255680
dc.description.abstractBACKGROUND: The transmissible spongiform encephalopathies (TSEs), otherwise known as the prion diseases, occur following the conversion of the normal cellular prion protein (PrPC) to an alternatively folded isoform (PrPSc). The accumulation of PrPSc 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 PrPSc. 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 PrPSc, but not by PrPC. 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 A2 (cPLA2) co-precipitated with PrPSc in ScGT1 cells. Furthermore, prion infection greatly increased both the phosphorylation of cPLA2 and prostaglandin E2 production. CONCLUSION: Prion infection, or the addition of PrPSc, increased the free cholesterol content of cells, a process that could not be replicated by the stimulation of cholesterol synthesis. The presence of PrPSc increased solubilisation of free cholesterol in cell membranes and affected their function. It increased activation of the PLA2 pathway, previously implicated in PrPSc formation and in PrPSc-mediated neurotoxicity. These observations suggest that the neuropathogenesis of prion diseases results from PrPSc altering cholesterol-sensitive processes. Furthermore, they raise the possibility that disturbances in membrane cholesterol are major triggering events in neurodegenerative diseases.
dc.languageEnglish
dc.publisherBIOMED CENTRAL LTD
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleSequestration of free cholesterol in cell membranes by prions correlates with cytoplasmic phospholipase A(2) activation
dc.typeJournal Article
dc.identifier.doi10.1186/1741-7007-6-8
melbourne.affiliation.departmentFlorey Department of Neuroscience and Mental Health
melbourne.source.titleBMC Biology
melbourne.source.volume6
melbourne.source.issue1
dc.rights.licenseCC BY
melbourne.elementsid1196553
melbourne.contributor.authorTayebi, Mourad
dc.identifier.eissn1741-7007
melbourne.accessrightsOpen Access


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record