A glycosylphosphatidylinositol analogue reduced prion-derived peptide mediated activation of cytoplasmic phospholipase A2, synapse degeneration and neuronal death.
The pathogenesis of prion diseases includes synapse degeneration and neuronal death. Here we report that pre-treatment with glucosamine-phosphatidylinositol (glucosamine-PI), a synthetic analogue of the glycosylphosphatidylinositol (GPI) anchor that attaches the prion protein (PrP(C)) to plasma membranes, increased the resistance of cultured cortical neurones to the toxic effects of the prion-derived peptide PrP82-146. Pre-treatment with glucosamine-PI reduced the PrP82-146 induced activation of cytoplasmic phospholipase A(2) (cPLA(2)), activation of caspase-3 and synapse degeneration. The addition of glucosamine-PI significantly increased the amount of cholesterol within neuronal membranes consistent with the hypothesis that GPI anchors sequester cholesterol. Whereas in untreated neurones PrP82-146 was found within lipid rafts, in glucosamine-PI treated neurones most PrP82-146 was found in the normal cell membrane and was rerouted into the lysosomes. Complex GPI anchors isolated from PrP(C), Thy-1 or CD55 were also protective against PrP82-146. We conclude that glucosamine-PI, or isolated GPI anchors, can modify local membrane micro-environments that are important in the initiation of signalling events that mediate PrP82-146 induced neurodegeneration.
Bate
Clive
C
Department of Pathology and Infectious Diseases, Royal Veterinary College, North Mymms, Herts, UK. cbate@rvc.ac.uk
Tayebi
Mourad
M
Williams
Alun
A
D000818:Animals; D018958:CD55 Antigens / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000502:physiology; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010455:Peptides / Q000378:metabolism; D010716:Phosphatidylinositols / Q000494:pharmacology*; D054467:Phospholipases A2 / Q000378:metabolism*; D018621:PrPC Proteins / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D018800:Thy-1 Antigens / Q000378:metabolism
D018958:CD55 Antigens; D002491:Central Nervous System Agents; D017261:Glycosylphosphatidylinositols; D010455:Peptides; D010716:Phosphatidylinositols; D018621:PrPC Proteins; D018800:Thy-1 Antigens; D002784:Cholesterol; D054467:Phospholipases A2