Role of glycosylphosphatidylinositols in the activation of phospholipase A2 and the neurotoxicity of prions
| العنوان: | Role of glycosylphosphatidylinositols in the activation of phospholipase A2 and the neurotoxicity of prions |
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| المؤلفون: | Alun Williams, Clive Bate |
| المصدر: | Journal of General Virology. 85:3797-3804 |
| بيانات النشر: | Microbiology Society, 2004. |
| سنة النشر: | 2004 |
| مصطلحات موضوعية: | Glycosylphosphatidylinositols, Prions, animal diseases, Apoptosis, Dinoprostone, Phospholipases A, Mice, chemistry.chemical_compound, Phospholipase A2, Cell Line, Tumor, Virology, medicine, Animals, Phosphatidylinositol, Prostaglandin E2, Neurons, Microglia, biology, Caspase 3, Neurodegeneration, Neurotoxicity, medicine.disease, Caspase Inhibitors, nervous system diseases, Sialic acid, Enzyme Activation, Phospholipases A2, medicine.anatomical_structure, Biochemistry, chemistry, Nerve Degeneration, biology.protein, Arachidonic acid, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1465-2099 0022-1317 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9776e3b7d0a445671d69419fe426aae2Test https://doi.org/10.1099/vir.0.80366-0Test |
| رقم الانضمام: | edsair.doi.dedup.....9776e3b7d0a445671d69419fe426aae2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14652099 00221317 |
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