title: Does the tail wag the dog? How the structure of a glycosylphosphatidylinositol anchor affects prion formation.
abstract: There is increasing interest in the role of the glycosylphosphatidylinositol (GPI) anchor attached to the cellular prion protein (PrP(C)). Since GPI anchors can alter protein targeting, trafficking and cell signaling, our recent study examined how the structure of the GPI anchor affected prion formation. PrP(C) containing a GPI anchor from which the sialic acid had been removed (desialylated PrP(C)) was not converted to PrP(Sc) in prion-infected neuronal cell lines and in scrapie-infected primary cortical neurons. In uninfected neurons desialylated PrP(C) was associated with greater concentrations of gangliosides and cholesterol than PrP(C). In addition, the targeting of desialylated PrP(C) to lipid rafts showed greater resistance to cholesterol depletion than PrP(C). The presence of desialylated PrP(C) caused the dissociation of cytoplasmic phospholipase A2 (cPLA2) from PrP-containing lipid rafts, reduced the activation of cPLA2 and inhibited PrP(Sc) production. We conclude that the sialic acid moiety of the GPI attached to PrP(C) modifies local membrane microenvironments that are important in PrP-mediated cell signaling and PrP(Sc) formation.
authors.affiliation: a Department of Pathology and Pathogen Biology , Royal Veterinary College , North Mymms, Herts , UK ;
authors.forename: Clive
authors.initials: C
authors.lastname: Bate
authors.affiliation: a Department of Pathology and Pathogen Biology , Royal Veterinary College , North Mymms, Herts , UK ;
authors.forename: William
authors.initials: W
authors.lastname: Nolan
authors.affiliation: b Department of Veterinary Medicine , University of Cambridge , Cambridge , UK.
authors.forename: Alun
authors.initials: A
authors.lastname: Williams
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006801:Humans; D054467:Phospholipases A2 / Q000378:metabolism*; D018621:PrPC Proteins / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism*
chemical_list: D017261:Glycosylphosphatidylinositols; D018621:PrPC Proteins; D002784:Cholesterol; D054467:Phospholipases A2
keywords: Cholesterol; glycosylphosphatidylinositols; phospholipase A2; prion; sialic acid