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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
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.
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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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