Glypican-1 mediates both prion protein lipid raft association and disease isoform formation

David R. Taylor, Isobel J. Whitehouse, Nigel M. Hooper

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    In prion diseases, the cellular form of the prion protein, PrPC, undergoes a conformational conversion to the infectious isoform, PrP Sc. PrPC associates with lipid rafts through its glycosyl-phosphatidylinositol (GPI) anchor and a region in its N-terminal domain which also binds to heparan sulfate proteoglycans (HSPGs). We show that heparin displaces PrPC from rafts and promotes its endocytosis, suggesting that heparin competes with an endogenous raft-resident HSPG for binding to PrPC. We then utilised a transmembrane-anchored form of PrP (PrP-TM), which is targeted to rafts solely by its N-terminal domain, to show that both heparin and phosphatidylinositol-specific phospholipase C can inhibit its association with detergent-resistant rafts, implying that a GPI-anchored HSPG targets PrP C to rafts. Depletion of the major neuronal GPI-anchored HSPG, glypican-1, significantly reduced the raft association of PrP-TM and displaced PrPC from rafts, promoting its endocytosis. Glypican-1 and PrP C colocalised on the cell surface and both PrPC and PrPSc co-immunoprecipitated with glypican-1. Critically, treatment of scrapie-infected N2a cells with glypican-1 siRNA significantly reduced PrP Sc formation. In contrast, depletion of glypican-1 did not alter the inhibitory effect of PrPC on the β-secretase cleavage of the Alzheimer's amyloid precursor protein. These data indicate that glypican-1 is a novel cellular cofactor for prion conversion and we propose that it acts as a scaffold facilitating the interaction of PrPC and PrPSc in lipid rafts. © 2009 Taylor et al.
    Original languageEnglish
    Article numbere1000666
    JournalPL o S Pathogens
    Issue number11
    Publication statusPublished - Nov 2009

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