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Neuropharmacology. 2010 Jul-Aug;59(1-2):93-9. doi: 10.1016/j.neuropharm.2010.04.002. Epub 2010 Apr 14.

A glycosylphosphatidylinositol analogue reduced prion-derived peptide mediated activation of cytoplasmic phospholipase A2, synapse degeneration and neuronal death.

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1
Department of Pathology and Infectious Diseases, Royal Veterinary College, North Mymms, Herts, UK. cbate@rvc.ac.uk

Abstract

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.

[Indexed for MEDLINE]

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