Glycosaminoglycan sulphation affects the seeded misfolding of a mutant prion protein.

<h4>Background</h4>The accumulation of protease resistant conformers of the prion protein (PrP(res)) is a key pathological feature of prion diseases. Polyanions, including RNA and glycosaminoglycans have been identified as factors that contribute to the propagation, transmission and path...

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Autores principales: Victoria A Lawson, Brooke Lumicisi, Jeremy Welton, Dorothy Machalek, Katrina Gouramanis, Helen M Klemm, James D Stewart, Colin L Masters, David E Hoke, Steven J Collins, Andrew F Hill
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spelling oai:doaj.org-article:1053ce57cef44fceb9562c4a059e980a2021-11-18T06:35:47ZGlycosaminoglycan sulphation affects the seeded misfolding of a mutant prion protein.1932-620310.1371/journal.pone.0012351https://doaj.org/article/1053ce57cef44fceb9562c4a059e980a2010-08-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20808809/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The accumulation of protease resistant conformers of the prion protein (PrP(res)) is a key pathological feature of prion diseases. Polyanions, including RNA and glycosaminoglycans have been identified as factors that contribute to the propagation, transmission and pathogenesis of prion disease. Recent studies have suggested that the contribution of these cofactors to prion propagation may be species specific.<h4>Methodology/principal finding</h4>In this study a cell-free assay was used to investigate the molecular basis of polyanion stimulated PrP(res) formation using brain tissue or cell line derived murine PrP. Enzymatic depletion of endogenous nucleic acids or heparan sulphate (HS) from the PrP(C) substrate was found to specifically prevent PrP(res) formation seeded by mouse derived PrP(Sc). Modification of the negative charge afforded by the sulphation of glycosaminoglycans increased the ability of a familial PrP mutant to act as a substrate for PrP(res) formation, while having no effect on PrP(res) formed by wildtype PrP. This difference may be due to the observed differences in the binding of wild type and mutant PrP for glycosaminoglycans.<h4>Conclusions/significance</h4>Cofactor requirements for PrP(res) formation are host species and prion strain specific and affected by disease associated mutations of the prion protein. This may explain both species and strain dependent propagation characteristics and provide insights into the underlying mechanisms of familial prion disease. It further highlights the challenge of designing effective therapeutics against a disease which effects a range of mammalian species, caused by range of aetiologies and prion strains.Victoria A LawsonBrooke LumicisiJeremy WeltonDorothy MachalekKatrina GouramanisHelen M KlemmJames D StewartColin L MastersDavid E HokeSteven J CollinsAndrew F HillPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 8, p e12351 (2010)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Victoria A Lawson
Brooke Lumicisi
Jeremy Welton
Dorothy Machalek
Katrina Gouramanis
Helen M Klemm
James D Stewart
Colin L Masters
David E Hoke
Steven J Collins
Andrew F Hill
Glycosaminoglycan sulphation affects the seeded misfolding of a mutant prion protein.
description <h4>Background</h4>The accumulation of protease resistant conformers of the prion protein (PrP(res)) is a key pathological feature of prion diseases. Polyanions, including RNA and glycosaminoglycans have been identified as factors that contribute to the propagation, transmission and pathogenesis of prion disease. Recent studies have suggested that the contribution of these cofactors to prion propagation may be species specific.<h4>Methodology/principal finding</h4>In this study a cell-free assay was used to investigate the molecular basis of polyanion stimulated PrP(res) formation using brain tissue or cell line derived murine PrP. Enzymatic depletion of endogenous nucleic acids or heparan sulphate (HS) from the PrP(C) substrate was found to specifically prevent PrP(res) formation seeded by mouse derived PrP(Sc). Modification of the negative charge afforded by the sulphation of glycosaminoglycans increased the ability of a familial PrP mutant to act as a substrate for PrP(res) formation, while having no effect on PrP(res) formed by wildtype PrP. This difference may be due to the observed differences in the binding of wild type and mutant PrP for glycosaminoglycans.<h4>Conclusions/significance</h4>Cofactor requirements for PrP(res) formation are host species and prion strain specific and affected by disease associated mutations of the prion protein. This may explain both species and strain dependent propagation characteristics and provide insights into the underlying mechanisms of familial prion disease. It further highlights the challenge of designing effective therapeutics against a disease which effects a range of mammalian species, caused by range of aetiologies and prion strains.
format article
author Victoria A Lawson
Brooke Lumicisi
Jeremy Welton
Dorothy Machalek
Katrina Gouramanis
Helen M Klemm
James D Stewart
Colin L Masters
David E Hoke
Steven J Collins
Andrew F Hill
author_facet Victoria A Lawson
Brooke Lumicisi
Jeremy Welton
Dorothy Machalek
Katrina Gouramanis
Helen M Klemm
James D Stewart
Colin L Masters
David E Hoke
Steven J Collins
Andrew F Hill
author_sort Victoria A Lawson
title Glycosaminoglycan sulphation affects the seeded misfolding of a mutant prion protein.
title_short Glycosaminoglycan sulphation affects the seeded misfolding of a mutant prion protein.
title_full Glycosaminoglycan sulphation affects the seeded misfolding of a mutant prion protein.
title_fullStr Glycosaminoglycan sulphation affects the seeded misfolding of a mutant prion protein.
title_full_unstemmed Glycosaminoglycan sulphation affects the seeded misfolding of a mutant prion protein.
title_sort glycosaminoglycan sulphation affects the seeded misfolding of a mutant prion protein.
publisher Public Library of Science (PLoS)
publishDate 2010
url https://doaj.org/article/1053ce57cef44fceb9562c4a059e980a
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