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Glypican-1 Mediates Both Prion Protein Lipid Raft Association and Disease Isoform Formation

In prion diseases, the cellular form of the prion protein, PrP(C), undergoes a conformational conversion to the infectious isoform, PrP(Sc). PrP(C) associates with lipid rafts through its glycosyl-phosphatidylinositol (GPI) anchor and a region in its N-terminal domain which also binds to heparan sul...

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Autores principales: Taylor, David R., Whitehouse, Isobel J., Hooper, Nigel M.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773931/
https://www.ncbi.nlm.nih.gov/pubmed/19936054
http://dx.doi.org/10.1371/journal.ppat.1000666
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author Taylor, David R.
Whitehouse, Isobel J.
Hooper, Nigel M.
author_facet Taylor, David R.
Whitehouse, Isobel J.
Hooper, Nigel M.
author_sort Taylor, David R.
collection PubMed
description In prion diseases, the cellular form of the prion protein, PrP(C), undergoes a conformational conversion to the infectious isoform, PrP(Sc). PrP(C) 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 PrP(C) from rafts and promotes its endocytosis, suggesting that heparin competes with an endogenous raft-resident HSPG for binding to PrP(C). 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 PrP(C) from rafts, promoting its endocytosis. Glypican-1 and PrP(C) colocalised on the cell surface and both PrP(C) and PrP(Sc) 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 PrP(C) 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 PrP(C) and PrP(Sc) in lipid rafts.
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spelling pubmed-27739312009-11-24 Glypican-1 Mediates Both Prion Protein Lipid Raft Association and Disease Isoform Formation Taylor, David R. Whitehouse, Isobel J. Hooper, Nigel M. PLoS Pathog Research Article In prion diseases, the cellular form of the prion protein, PrP(C), undergoes a conformational conversion to the infectious isoform, PrP(Sc). PrP(C) 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 PrP(C) from rafts and promotes its endocytosis, suggesting that heparin competes with an endogenous raft-resident HSPG for binding to PrP(C). 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 PrP(C) from rafts, promoting its endocytosis. Glypican-1 and PrP(C) colocalised on the cell surface and both PrP(C) and PrP(Sc) 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 PrP(C) 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 PrP(C) and PrP(Sc) in lipid rafts. Public Library of Science 2009-11-20 /pmc/articles/PMC2773931/ /pubmed/19936054 http://dx.doi.org/10.1371/journal.ppat.1000666 Text en Taylor et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Taylor, David R.
Whitehouse, Isobel J.
Hooper, Nigel M.
Glypican-1 Mediates Both Prion Protein Lipid Raft Association and Disease Isoform Formation
title Glypican-1 Mediates Both Prion Protein Lipid Raft Association and Disease Isoform Formation
title_full Glypican-1 Mediates Both Prion Protein Lipid Raft Association and Disease Isoform Formation
title_fullStr Glypican-1 Mediates Both Prion Protein Lipid Raft Association and Disease Isoform Formation
title_full_unstemmed Glypican-1 Mediates Both Prion Protein Lipid Raft Association and Disease Isoform Formation
title_short Glypican-1 Mediates Both Prion Protein Lipid Raft Association and Disease Isoform Formation
title_sort glypican-1 mediates both prion protein lipid raft association and disease isoform formation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773931/
https://www.ncbi.nlm.nih.gov/pubmed/19936054
http://dx.doi.org/10.1371/journal.ppat.1000666
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