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Early stage prion assembly involves two subpopulations with different quaternary structures and a secondary templating pathway
The dynamics of aggregation and structural diversification of misfolded, host-encoded proteins in neurodegenerative diseases are poorly understood. In many of these disorders, including Alzheimer’s, Parkinson’s and prion diseases, the misfolded proteins are self-organized into conformationally disti...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778151/ https://www.ncbi.nlm.nih.gov/pubmed/31602412 http://dx.doi.org/10.1038/s42003-019-0608-y |
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author | Igel-Egalon, Angélique Laferrière, Florent Moudjou, Mohammed Bohl, Jan Mezache, Mathieu Knäpple, Tina Herzog, Laetitia Reine, Fabienne Jas-Duval, Christelle Doumic, Marie Rezaei, Human Béringue, Vincent |
author_facet | Igel-Egalon, Angélique Laferrière, Florent Moudjou, Mohammed Bohl, Jan Mezache, Mathieu Knäpple, Tina Herzog, Laetitia Reine, Fabienne Jas-Duval, Christelle Doumic, Marie Rezaei, Human Béringue, Vincent |
author_sort | Igel-Egalon, Angélique |
collection | PubMed |
description | The dynamics of aggregation and structural diversification of misfolded, host-encoded proteins in neurodegenerative diseases are poorly understood. In many of these disorders, including Alzheimer’s, Parkinson’s and prion diseases, the misfolded proteins are self-organized into conformationally distinct assemblies or strains. The existence of intrastrain structural heterogeneity is increasingly recognized. However, the underlying processes of emergence and coevolution of structurally distinct assemblies are not mechanistically understood. Here, we show that early prion replication generates two subsets of structurally different assemblies by two sequential processes of formation, regardless of the strain considered. The first process corresponds to a quaternary structural convergence, by reducing the parental strain polydispersity to generate small oligomers. The second process transforms these oligomers into larger ones, by a secondary autocatalytic templating pathway requiring the prion protein. This pathway provides mechanistic insights into prion structural diversification, a key determinant for prion adaptation and toxicity. |
format | Online Article Text |
id | pubmed-6778151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-67781512019-10-10 Early stage prion assembly involves two subpopulations with different quaternary structures and a secondary templating pathway Igel-Egalon, Angélique Laferrière, Florent Moudjou, Mohammed Bohl, Jan Mezache, Mathieu Knäpple, Tina Herzog, Laetitia Reine, Fabienne Jas-Duval, Christelle Doumic, Marie Rezaei, Human Béringue, Vincent Commun Biol Article The dynamics of aggregation and structural diversification of misfolded, host-encoded proteins in neurodegenerative diseases are poorly understood. In many of these disorders, including Alzheimer’s, Parkinson’s and prion diseases, the misfolded proteins are self-organized into conformationally distinct assemblies or strains. The existence of intrastrain structural heterogeneity is increasingly recognized. However, the underlying processes of emergence and coevolution of structurally distinct assemblies are not mechanistically understood. Here, we show that early prion replication generates two subsets of structurally different assemblies by two sequential processes of formation, regardless of the strain considered. The first process corresponds to a quaternary structural convergence, by reducing the parental strain polydispersity to generate small oligomers. The second process transforms these oligomers into larger ones, by a secondary autocatalytic templating pathway requiring the prion protein. This pathway provides mechanistic insights into prion structural diversification, a key determinant for prion adaptation and toxicity. Nature Publishing Group UK 2019-10-04 /pmc/articles/PMC6778151/ /pubmed/31602412 http://dx.doi.org/10.1038/s42003-019-0608-y Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Igel-Egalon, Angélique Laferrière, Florent Moudjou, Mohammed Bohl, Jan Mezache, Mathieu Knäpple, Tina Herzog, Laetitia Reine, Fabienne Jas-Duval, Christelle Doumic, Marie Rezaei, Human Béringue, Vincent Early stage prion assembly involves two subpopulations with different quaternary structures and a secondary templating pathway |
title | Early stage prion assembly involves two subpopulations with different quaternary structures and a secondary templating pathway |
title_full | Early stage prion assembly involves two subpopulations with different quaternary structures and a secondary templating pathway |
title_fullStr | Early stage prion assembly involves two subpopulations with different quaternary structures and a secondary templating pathway |
title_full_unstemmed | Early stage prion assembly involves two subpopulations with different quaternary structures and a secondary templating pathway |
title_short | Early stage prion assembly involves two subpopulations with different quaternary structures and a secondary templating pathway |
title_sort | early stage prion assembly involves two subpopulations with different quaternary structures and a secondary templating pathway |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778151/ https://www.ncbi.nlm.nih.gov/pubmed/31602412 http://dx.doi.org/10.1038/s42003-019-0608-y |
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