Sequestration of free cholesterol in cell membranes by prions correlates with cytoplasmic phospholipase A2 activation
| العنوان: | Sequestration of free cholesterol in cell membranes by prions correlates with cytoplasmic phospholipase A2 activation |
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| المؤلفون: | Alun Williams, Clive Bate, Mourad Tayebi |
| المصدر: | BMC Biology BMC Biology, Vol 6, Iss 1, p 8 (2008) |
| بيانات النشر: | BioMed Central, 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Cytoplasm, PrPSc Proteins, Physiology, animal diseases, Plant Science, Prion Diseases, Cell membrane, chemistry.chemical_compound, Mice, Structural Biology, lcsh:QH301-705.5, Neurons, Agricultural and Biological Sciences(all), Neurodegeneration, medicine.anatomical_structure, Cholesterol, Biochemistry, Phosphorylation, lipids (amino acids, peptides, and proteins), General Agricultural and Biological Sciences, Biotechnology, Research Article, Enzyme-Linked Immunosorbent Assay, Biology, General Biochemistry, Genetics and Molecular Biology, Cell Line, Phospholipase A2, medicine, Animals, Immunoprecipitation, PrPC Proteins, Ecology, Evolution, Behavior and Systematics, Analysis of Variance, Biochemistry, Genetics and Molecular Biology(all), Cell Membrane, Neurotoxicity, Cell Biology, medicine.disease, Embryo, Mammalian, nervous system diseases, Enzyme Activation, Phospholipases A2, chemistry, lcsh:Biology (General), nervous system, Cell culture, biology.protein, Developmental Biology |
| الوصف: | Background 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. |
| اللغة: | English |
| تدمد: | 1741-7007 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c273dcc3ce58530abeda9870cd8b41e9Test http://europepmc.org/articles/PMC2270799Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c273dcc3ce58530abeda9870cd8b41e9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17417007 |
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