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 (PrPC) 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 A2 (cPLA2), 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 PrPC, 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.