Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions.

Prion diseases, particularly sporadic cases, pose a challenge due to their complex nature and heterogeneity. The underlying mechanism of the spontaneous conversion from PrPC to PrPSc, the hallmark of prion diseases, remains elusive. To shed light on this process and the involvement of cofactors, we...

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Main Authors: Miguel Ángel Pérez-Castro, Hasier Eraña, Enric Vidal, Jorge M Charco, Nuria L Lorenzo, Nuno Gonçalves-Anjo, Josu Galarza-Ahumada, Carlos M Díaz-Domínguez, Patricia Piñeiro, Ezequiel González-Miranda, Samanta Giler, Glenn Telling, Manuel A Sánchez-Martín, Joseba Garrido, Mariví Geijo, Jesús R Requena, Joaquín Castilla
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2025-01-01
Series:PLoS Pathogens
Online Access:https://doi.org/10.1371/journal.ppat.1012890
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author Miguel Ángel Pérez-Castro
Hasier Eraña
Enric Vidal
Jorge M Charco
Nuria L Lorenzo
Nuno Gonçalves-Anjo
Josu Galarza-Ahumada
Carlos M Díaz-Domínguez
Patricia Piñeiro
Ezequiel González-Miranda
Samanta Giler
Glenn Telling
Manuel A Sánchez-Martín
Joseba Garrido
Mariví Geijo
Jesús R Requena
Joaquín Castilla
author_facet Miguel Ángel Pérez-Castro
Hasier Eraña
Enric Vidal
Jorge M Charco
Nuria L Lorenzo
Nuno Gonçalves-Anjo
Josu Galarza-Ahumada
Carlos M Díaz-Domínguez
Patricia Piñeiro
Ezequiel González-Miranda
Samanta Giler
Glenn Telling
Manuel A Sánchez-Martín
Joseba Garrido
Mariví Geijo
Jesús R Requena
Joaquín Castilla
author_sort Miguel Ángel Pérez-Castro
collection DOAJ
description Prion diseases, particularly sporadic cases, pose a challenge due to their complex nature and heterogeneity. The underlying mechanism of the spontaneous conversion from PrPC to PrPSc, the hallmark of prion diseases, remains elusive. To shed light on this process and the involvement of cofactors, we have developed an in vitro system that faithfully mimics spontaneous prion misfolding using minimal components. By employing this PMSA methodology and introducing an isoleucine residue at position 108 in mouse PrP, we successfully generated recombinant murine prion strains with distinct biochemical and biological properties. Our study aimed to explore the influence of a polyanionic cofactor in modulating strain selection and infectivity in de novo-generated synthetic prions. These results not only validate PMSA as a robust method for generating diverse bona fide recombinant prions but also emphasize the significance of cofactors in shaping specific prion conformers capable of crossing species barriers. Interestingly, once these conformers are established, our findings suggest that cofactors are not necessary for their infectivity. This research provides valuable insights into the propagation and maintenance of the pathobiological features of cross-species transmissible recombinant murine prion and highlights the intricate interplay between cofactors and prion strain characteristics.
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issn 1553-7366
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language English
publishDate 2025-01-01
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spelling doaj-art-7ecfd6dccd0d41e08f6cfbe9930c714e2025-02-05T05:30:53ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-01-01211e101289010.1371/journal.ppat.1012890Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions.Miguel Ángel Pérez-CastroHasier ErañaEnric VidalJorge M CharcoNuria L LorenzoNuno Gonçalves-AnjoJosu Galarza-AhumadaCarlos M Díaz-DomínguezPatricia PiñeiroEzequiel González-MirandaSamanta GilerGlenn TellingManuel A Sánchez-MartínJoseba GarridoMariví GeijoJesús R RequenaJoaquín CastillaPrion diseases, particularly sporadic cases, pose a challenge due to their complex nature and heterogeneity. The underlying mechanism of the spontaneous conversion from PrPC to PrPSc, the hallmark of prion diseases, remains elusive. To shed light on this process and the involvement of cofactors, we have developed an in vitro system that faithfully mimics spontaneous prion misfolding using minimal components. By employing this PMSA methodology and introducing an isoleucine residue at position 108 in mouse PrP, we successfully generated recombinant murine prion strains with distinct biochemical and biological properties. Our study aimed to explore the influence of a polyanionic cofactor in modulating strain selection and infectivity in de novo-generated synthetic prions. These results not only validate PMSA as a robust method for generating diverse bona fide recombinant prions but also emphasize the significance of cofactors in shaping specific prion conformers capable of crossing species barriers. Interestingly, once these conformers are established, our findings suggest that cofactors are not necessary for their infectivity. This research provides valuable insights into the propagation and maintenance of the pathobiological features of cross-species transmissible recombinant murine prion and highlights the intricate interplay between cofactors and prion strain characteristics.https://doi.org/10.1371/journal.ppat.1012890
spellingShingle Miguel Ángel Pérez-Castro
Hasier Eraña
Enric Vidal
Jorge M Charco
Nuria L Lorenzo
Nuno Gonçalves-Anjo
Josu Galarza-Ahumada
Carlos M Díaz-Domínguez
Patricia Piñeiro
Ezequiel González-Miranda
Samanta Giler
Glenn Telling
Manuel A Sánchez-Martín
Joseba Garrido
Mariví Geijo
Jesús R Requena
Joaquín Castilla
Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions.
PLoS Pathogens
title Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions.
title_full Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions.
title_fullStr Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions.
title_full_unstemmed Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions.
title_short Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions.
title_sort cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions
url https://doi.org/10.1371/journal.ppat.1012890
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