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Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation

Among transmissible spongiform encephalopathies or prion diseases affecting humans, sporadic forms such as sporadic Creutzfeldt–Jakob disease are the vast majority. Unlike genetic or acquired forms of the disease, these idiopathic forms occur seemingly due to a random event of spontaneous misfolding...

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Autores principales: Eraña, Hasier, Díaz-Domínguez, Carlos M., Charco, Jorge M., Vidal, Enric, González-Miranda, Ezequiel, Pérez-Castro, Miguel A., Piñeiro, Patricia, López-Moreno, Rafael, Sampedro-Torres-Quevedo, Cristina, Fernández-Veiga, Leire, Tasis-Galarza, Juan, Lorenzo, Nuria L., Santini-Santiago, Aileen, Lázaro, Melisa, García-Martínez, Sandra, Gonçalves-Anjo, Nuno, San-Juan-Ansoleaga, Maitena, Galarza-Ahumada, Josu, Fernández-Muñoz, Eva, Giler, Samanta, Valle, Mikel, Telling, Glenn C., Geijó, Mariví, Requena, Jesús R., Castilla, Joaquín
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10486007/
https://www.ncbi.nlm.nih.gov/pubmed/37679832
http://dx.doi.org/10.1186/s40478-023-01640-8
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author Eraña, Hasier
Díaz-Domínguez, Carlos M.
Charco, Jorge M.
Vidal, Enric
González-Miranda, Ezequiel
Pérez-Castro, Miguel A.
Piñeiro, Patricia
López-Moreno, Rafael
Sampedro-Torres-Quevedo, Cristina
Fernández-Veiga, Leire
Tasis-Galarza, Juan
Lorenzo, Nuria L.
Santini-Santiago, Aileen
Lázaro, Melisa
García-Martínez, Sandra
Gonçalves-Anjo, Nuno
San-Juan-Ansoleaga, Maitena
Galarza-Ahumada, Josu
Fernández-Muñoz, Eva
Giler, Samanta
Valle, Mikel
Telling, Glenn C.
Geijó, Mariví
Requena, Jesús R.
Castilla, Joaquín
author_facet Eraña, Hasier
Díaz-Domínguez, Carlos M.
Charco, Jorge M.
Vidal, Enric
González-Miranda, Ezequiel
Pérez-Castro, Miguel A.
Piñeiro, Patricia
López-Moreno, Rafael
Sampedro-Torres-Quevedo, Cristina
Fernández-Veiga, Leire
Tasis-Galarza, Juan
Lorenzo, Nuria L.
Santini-Santiago, Aileen
Lázaro, Melisa
García-Martínez, Sandra
Gonçalves-Anjo, Nuno
San-Juan-Ansoleaga, Maitena
Galarza-Ahumada, Josu
Fernández-Muñoz, Eva
Giler, Samanta
Valle, Mikel
Telling, Glenn C.
Geijó, Mariví
Requena, Jesús R.
Castilla, Joaquín
author_sort Eraña, Hasier
collection PubMed
description Among transmissible spongiform encephalopathies or prion diseases affecting humans, sporadic forms such as sporadic Creutzfeldt–Jakob disease are the vast majority. Unlike genetic or acquired forms of the disease, these idiopathic forms occur seemingly due to a random event of spontaneous misfolding of the cellular PrP (PrP(C)) into the pathogenic isoform (PrP(Sc)). Currently, the molecular mechanisms that trigger and drive this event, which occurs in approximately one individual per million each year, remain completely unknown. Modelling this phenomenon in experimental settings is highly challenging due to its sporadic and rare occurrence. Previous attempts to model spontaneous prion misfolding in vitro have not been fully successful, as the spontaneous formation of prions is infrequent and stochastic, hindering the systematic study of the phenomenon. In this study, we present the first method that consistently induces spontaneous misfolding of recombinant PrP into bona fide prions within hours, providing unprecedented possibilities to investigate the mechanisms underlying sporadic prionopathies. By fine-tuning the Protein Misfolding Shaking Amplification method, which was initially developed to propagate recombinant prions, we have created a methodology that consistently produces spontaneously misfolded recombinant prions in 100% of the cases. Furthermore, this method gives rise to distinct strains and reveals the critical influence of charged surfaces in this process. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-023-01640-8.
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spelling pubmed-104860072023-09-09 Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation Eraña, Hasier Díaz-Domínguez, Carlos M. Charco, Jorge M. Vidal, Enric González-Miranda, Ezequiel Pérez-Castro, Miguel A. Piñeiro, Patricia López-Moreno, Rafael Sampedro-Torres-Quevedo, Cristina Fernández-Veiga, Leire Tasis-Galarza, Juan Lorenzo, Nuria L. Santini-Santiago, Aileen Lázaro, Melisa García-Martínez, Sandra Gonçalves-Anjo, Nuno San-Juan-Ansoleaga, Maitena Galarza-Ahumada, Josu Fernández-Muñoz, Eva Giler, Samanta Valle, Mikel Telling, Glenn C. Geijó, Mariví Requena, Jesús R. Castilla, Joaquín Acta Neuropathol Commun Research Among transmissible spongiform encephalopathies or prion diseases affecting humans, sporadic forms such as sporadic Creutzfeldt–Jakob disease are the vast majority. Unlike genetic or acquired forms of the disease, these idiopathic forms occur seemingly due to a random event of spontaneous misfolding of the cellular PrP (PrP(C)) into the pathogenic isoform (PrP(Sc)). Currently, the molecular mechanisms that trigger and drive this event, which occurs in approximately one individual per million each year, remain completely unknown. Modelling this phenomenon in experimental settings is highly challenging due to its sporadic and rare occurrence. Previous attempts to model spontaneous prion misfolding in vitro have not been fully successful, as the spontaneous formation of prions is infrequent and stochastic, hindering the systematic study of the phenomenon. In this study, we present the first method that consistently induces spontaneous misfolding of recombinant PrP into bona fide prions within hours, providing unprecedented possibilities to investigate the mechanisms underlying sporadic prionopathies. By fine-tuning the Protein Misfolding Shaking Amplification method, which was initially developed to propagate recombinant prions, we have created a methodology that consistently produces spontaneously misfolded recombinant prions in 100% of the cases. Furthermore, this method gives rise to distinct strains and reveals the critical influence of charged surfaces in this process. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-023-01640-8. BioMed Central 2023-09-07 /pmc/articles/PMC10486007/ /pubmed/37679832 http://dx.doi.org/10.1186/s40478-023-01640-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Eraña, Hasier
Díaz-Domínguez, Carlos M.
Charco, Jorge M.
Vidal, Enric
González-Miranda, Ezequiel
Pérez-Castro, Miguel A.
Piñeiro, Patricia
López-Moreno, Rafael
Sampedro-Torres-Quevedo, Cristina
Fernández-Veiga, Leire
Tasis-Galarza, Juan
Lorenzo, Nuria L.
Santini-Santiago, Aileen
Lázaro, Melisa
García-Martínez, Sandra
Gonçalves-Anjo, Nuno
San-Juan-Ansoleaga, Maitena
Galarza-Ahumada, Josu
Fernández-Muñoz, Eva
Giler, Samanta
Valle, Mikel
Telling, Glenn C.
Geijó, Mariví
Requena, Jesús R.
Castilla, Joaquín
Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation
title Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation
title_full Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation
title_fullStr Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation
title_full_unstemmed Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation
title_short Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation
title_sort understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10486007/
https://www.ncbi.nlm.nih.gov/pubmed/37679832
http://dx.doi.org/10.1186/s40478-023-01640-8
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