1887

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Volume 85, Issue 12

Role of glycosylphosphatidylinositols in the activation of phospholipase A and the neurotoxicity of prions Free

Abstract

Prion-induced neuronal injury is associated with prostaglandin E production, a process that can be reproduced in tissue-culture models of prion disease. In the present study, neuronal phospholipase A was activated by glycosylphosphatidylinositols (GPIs) isolated from the cellular prion protein (PrP) or from disease-associated isoforms (PrP), resulting in prostaglandin E production, but not by GPIs isolated from Thy-1. The ability of GPIs to activate neuronal phospholipase A 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 in response to a synthetic miniprion (sPrP106), a synthetic correlate of a PrP species found in Gerstmann–Sträussler–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 activation by PrP-GPIs as an early event in prion-induced neurodegeneration.

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2004-12-01
2024-12-04
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References

  1. Bate C. A. W., Kwiatkowski D. 1994; A monoclonal antibody that recognizes phosphatidylinositol inhibits induction of tumor necrosis factor alpha by different strains of Plasmodium falciparum . Infect Immun 62:5261–5266
     [Google Scholar]
  2. Bate C. A., Boshuizen R. S., Langeveld J. P. M., Williams A. 2002; Temporal and spatial relationship between the death of PrP-damaged neurones and microglial activation. Neuroreport 13:1695–1700 [CrossRef]
     [Google Scholar]
  3. Bate C., Salmona M., Diomede L., Williams A. 2004a; Squalestatin cures prion-infected neurons and protects against prion neurotoxicity. J Biol Chem 279:14983–14990 [CrossRef]
     [Google Scholar]
  4. Bate C. A., Salmona M., Williams A. 2004b; The role of platelet activating factor in prion and amyloid- β neurotoxicity. Neuroreport 15:509–513 [CrossRef]
     [Google Scholar]
  5. Bonetto V., Massignan T., Chiesa R. 8 other authors 2002; Synthetic miniprion PrP106. J Biol Chem 277:31327–31334 [CrossRef]
     [Google Scholar]
  6. Brown D. R., Herms J., Kretzschmar H. A. 1994; Mouse cortical cells lacking cellular PrP survive in culture with a neurotoxic PrP fragment. Neuroreport 5:2057–2060 [CrossRef]
     [Google Scholar]
  7. Brown D. R., Schmidt B., Kretzschmar H. A. 1996; Role of microglia and host prion protein in neurotoxicity of a prion protein fragment. Nature 380:345–347 [CrossRef]
     [Google Scholar]
  8. Forloni G., Angeretti N., Chiesa R., Monzani E., Salmona M., Bugiani O., Tagliavini F. 1993; Neurotoxicity of a prion protein fragment. Nature 362:543–546 [CrossRef]
     [Google Scholar]
  9. Frick W., Bauer A., Bauer J., Wied S., Müller G. 1998; Structure-activity relationship of synthetic phosphoinositolglycans mimicking metabolic insulin action. Biochemistry 37:13421–13436 [CrossRef]
     [Google Scholar]
  10. Giese A., Groschup M. H., Hess B., Kretzschmar H. A. 1995; Neuronal cell death in scrapie-infected mice is due to apoptosis. Brain Pathol 5:213–221 [CrossRef]
     [Google Scholar]
  11. Hope J., Shearman M. S., Baxter H. C., Chong A., Kelly S. M., Price N. C. 1996; Cytotoxicity of prion protein peptide (PrP106–126) differs in mechanism from the cytotoxic activity of the Alzheimer's disease amyloid peptide, A β 25–35. Neurodegeneration 5:1–11 [CrossRef]
     [Google Scholar]
  12. Jamieson E. C. A., Jeffrey M., Ironside J. W., Fraser J. R. 2001; Activation of Fas and caspase 3 precedes PrP accumulation in 87V scrapie. Neuroreport 12:3567–3572 [CrossRef]
     [Google Scholar]
  13. Jeffrey M., Halliday W. G., Bell J., Johnston A. R., Macleod N. K., Ingham C., Sayers A. R., Brown D. A., Fraser J. R. 2000; Synapse loss associated with abnormal PrP precedes neuronal degeneration in the scrapie-infected murine hippocampus. Neuropathol Appl Neurobiol 26:41–54 [CrossRef]
     [Google Scholar]
  14. Mayor S., Riezman H. 2004; Sorting GPI-anchored proteins. Nat Rev Mol Cell Biol 5:110–120 [CrossRef]
     [Google Scholar]
  15. Minghetti L., Greco A., Cardone F. 7 other authors 2000; Increased brain synthesis of prostaglandin E2 and F2-isoprostane in human and experimental transmissible spongiform encephalopathies. J Neuropathol Exp Neurol 59:866–871
     [Google Scholar]
  16. Minghetti L., Cardone F., Greco A., Puopolo M., Levi G., Green A. J. E., Knight R., Pocchiari M. 2002; Increased CSF levels of prostaglandin E2 in variant Creutzfeldt–Jakob disease. Neurology 58:127–129 [CrossRef]
     [Google Scholar]
  17. Pan K.-M., Baldwin M., Nguyen J. 8 other authors 1993; Conversion of α -helices into β -sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A 90:10962–10966 [CrossRef]
     [Google Scholar]
  18. Prusiner S. B. 1982; Novel proteinaceous infectious particles cause scrapie. Science 216:136–144 [CrossRef]
     [Google Scholar]
  19. Prusiner S. B. 1998; Prions. Proc Natl Acad Sci U S A 95:13363–13383 [CrossRef]
     [Google Scholar]
  20. Rudd P. M., Wormald M. R., Wing D. R., Prusiner S. B., Dwek R. A. 2001; Prion glycoprotein: structure, dynamics, and roles for the sugars. Biochemistry 40:3759–3766 [CrossRef]
     [Google Scholar]
  21. Salmona M., Morbin M., Massignan T. 14 other authors 2003; Structural properties of Gerstmann-Sträussler-Scheinker disease amyloid protein. J Biol Chem 278:48146–48153 [CrossRef]
     [Google Scholar]
  22. Solforosi L., Criado J. R., McGavern D. B. 12 other authors 2004; Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science 303:1514–1516 [CrossRef]
     [Google Scholar]
  23. Stahl N., Baldwin M. A., Hecker R., Pan K.-M., Burlingame A. L., Prusiner S. B. 1992; Glycosylinositol phospholipid anchors of the scrapie and cellular prion proteins contain sialic acid. Biochemistry 31:5043–5053 [CrossRef]
     [Google Scholar]
  24. Taraboulos A., Scott M., Semenov A., Avraham D., Laszlo L., Prusiner S. B. 1995; Cholesterol depletion and modification of COOH-terminal targeting sequence of the prion protein inhibit formation of the scrapie isoform. J Cell Biol 129:121–132 [CrossRef]
     [Google Scholar]
  25. Vijaykumar M., Naik R. S., Gowda D. C. 2001; Plasmodium falciparum glycosylphosphatidylinositol-induced TNF- α secretion by macrophages is mediated without membrane insertion or endocytosis. J Biol Chem 276:6909–6912 [CrossRef]
     [Google Scholar]
  26. Williams A. E., van Dam A.-M., Man-A-Hing W. K. H., Berkenbosch F., Eikelenboom P., Fraser H. 1994; Cytokines, prostaglandins and lipocortin-1 are present in the brains of scrapie-infected mice. Brain Res 654:200–206 [CrossRef]
     [Google Scholar]
  27. Williams A., Lucassen P. J., Ritchie D., Bruce M. 1997a; PrP deposition, microglial activation, and neuronal apoptosis in murine scrapie. Exp Neurol 144:433–438 [CrossRef]
     [Google Scholar]
  28. Williams A., Van Dam A.-M., Ritchie D., Eikelenboom P., Fraser H. 1997b; Immunocytochemical appearance of cytokines, prostaglandin E2 and lipocortin-1 in the CNS during the incubation period of murine scrapie correlates with progressive PrP accumulations. Brain Res 754:171–180 [CrossRef]
     [Google Scholar]
  29. Yang H. C., Farooqui A. A., Horrocks L. A. 1994; Effects of sialic acid and sialoglycoconjugates on cytosolic phospholipases A2 from bovine brain. Biochem Biophys Res Commun 199:1158–1166 [CrossRef]
     [Google Scholar]
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Role of glycosylphosphatidylinositols in the activation of phospholipase A2 and the neurotoxicity of prions
J. Gen. Virol. 85, 3797 (2004); https://doi.org/10.1099/vir.0.80366-0
/content/journal/jgv/10.1099/vir.0.80366-0
/content/journal/jgv/10.1099/vir.0.80366-0
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