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Protease-Sensitive Conformers in Broad Spectrum of Distinct PrP(Sc) Structures in Sporadic Creutzfeldt-Jakob Disease Are Indicator of Progression Rate

The origin, range, and structure of prions causing the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD), are largely unknown. To investigate the molecular mechanism responsible for the broad phenotypic variability of sCJD, we analyzed the conformational characteristics of p...

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Autores principales: Kim, Chae, Haldiman, Tracy, Cohen, Yvonne, Chen, Wei, Blevins, Janis, Sy, Man-Sun, Cohen, Mark, Safar, Jiri G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169556/
https://www.ncbi.nlm.nih.gov/pubmed/21931554
http://dx.doi.org/10.1371/journal.ppat.1002242
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author Kim, Chae
Haldiman, Tracy
Cohen, Yvonne
Chen, Wei
Blevins, Janis
Sy, Man-Sun
Cohen, Mark
Safar, Jiri G.
author_facet Kim, Chae
Haldiman, Tracy
Cohen, Yvonne
Chen, Wei
Blevins, Janis
Sy, Man-Sun
Cohen, Mark
Safar, Jiri G.
author_sort Kim, Chae
collection PubMed
description The origin, range, and structure of prions causing the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD), are largely unknown. To investigate the molecular mechanism responsible for the broad phenotypic variability of sCJD, we analyzed the conformational characteristics of protease-sensitive and protease-resistant fractions of the pathogenic prion protein (PrP(Sc)) using novel conformational methods derived from a conformation-dependent immunoassay (CDI). In 46 brains of patients homozygous for polymorphisms in the PRNP gene and exhibiting either Type 1 or Type 2 western blot pattern of the PrP(Sc), we identified an extensive array of PrP(Sc) structures that differ in protease sensitivity, display of critical domains, and conformational stability. Surprisingly, in sCJD cases homozygous for methionine or valine at codon 129 of the PRNP gene, the concentration and stability of protease-sensitive conformers of PrP(Sc) correlated with progression rate of the disease. These data indicate that sCJD brains exhibit a wide spectrum of PrP(Sc) structural states, and accordingly argue for a broad spectrum of prion strains coding for different phenotypes. The link between disease duration, levels, and stability of protease-sensitive conformers of PrP(Sc) suggests that these conformers play an important role in the pathogenesis of sCJD.
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spelling pubmed-31695562011-09-19 Protease-Sensitive Conformers in Broad Spectrum of Distinct PrP(Sc) Structures in Sporadic Creutzfeldt-Jakob Disease Are Indicator of Progression Rate Kim, Chae Haldiman, Tracy Cohen, Yvonne Chen, Wei Blevins, Janis Sy, Man-Sun Cohen, Mark Safar, Jiri G. PLoS Pathog Research Article The origin, range, and structure of prions causing the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD), are largely unknown. To investigate the molecular mechanism responsible for the broad phenotypic variability of sCJD, we analyzed the conformational characteristics of protease-sensitive and protease-resistant fractions of the pathogenic prion protein (PrP(Sc)) using novel conformational methods derived from a conformation-dependent immunoassay (CDI). In 46 brains of patients homozygous for polymorphisms in the PRNP gene and exhibiting either Type 1 or Type 2 western blot pattern of the PrP(Sc), we identified an extensive array of PrP(Sc) structures that differ in protease sensitivity, display of critical domains, and conformational stability. Surprisingly, in sCJD cases homozygous for methionine or valine at codon 129 of the PRNP gene, the concentration and stability of protease-sensitive conformers of PrP(Sc) correlated with progression rate of the disease. These data indicate that sCJD brains exhibit a wide spectrum of PrP(Sc) structural states, and accordingly argue for a broad spectrum of prion strains coding for different phenotypes. The link between disease duration, levels, and stability of protease-sensitive conformers of PrP(Sc) suggests that these conformers play an important role in the pathogenesis of sCJD. Public Library of Science 2011-09-08 /pmc/articles/PMC3169556/ /pubmed/21931554 http://dx.doi.org/10.1371/journal.ppat.1002242 Text en Kim 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
Kim, Chae
Haldiman, Tracy
Cohen, Yvonne
Chen, Wei
Blevins, Janis
Sy, Man-Sun
Cohen, Mark
Safar, Jiri G.
Protease-Sensitive Conformers in Broad Spectrum of Distinct PrP(Sc) Structures in Sporadic Creutzfeldt-Jakob Disease Are Indicator of Progression Rate
title Protease-Sensitive Conformers in Broad Spectrum of Distinct PrP(Sc) Structures in Sporadic Creutzfeldt-Jakob Disease Are Indicator of Progression Rate
title_full Protease-Sensitive Conformers in Broad Spectrum of Distinct PrP(Sc) Structures in Sporadic Creutzfeldt-Jakob Disease Are Indicator of Progression Rate
title_fullStr Protease-Sensitive Conformers in Broad Spectrum of Distinct PrP(Sc) Structures in Sporadic Creutzfeldt-Jakob Disease Are Indicator of Progression Rate
title_full_unstemmed Protease-Sensitive Conformers in Broad Spectrum of Distinct PrP(Sc) Structures in Sporadic Creutzfeldt-Jakob Disease Are Indicator of Progression Rate
title_short Protease-Sensitive Conformers in Broad Spectrum of Distinct PrP(Sc) Structures in Sporadic Creutzfeldt-Jakob Disease Are Indicator of Progression Rate
title_sort protease-sensitive conformers in broad spectrum of distinct prp(sc) structures in sporadic creutzfeldt-jakob disease are indicator of progression rate
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169556/
https://www.ncbi.nlm.nih.gov/pubmed/21931554
http://dx.doi.org/10.1371/journal.ppat.1002242
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