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Open Access 01-12-2023 | Research

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

Authors: Hasier Eraña, Carlos M. Díaz-Domínguez, Jorge M. Charco, Enric Vidal, Ezequiel González-Miranda, Miguel A. Pérez-Castro, Patricia Piñeiro, Rafael López-Moreno, Cristina Sampedro-Torres-Quevedo, Leire Fernández-Veiga, Juan Tasis-Galarza, Nuria L. Lorenzo, Aileen Santini-Santiago, Melisa Lázaro, Sandra García-Martínez, Nuno Gonçalves-Anjo, Maitena San-Juan-Ansoleaga, Josu Galarza-Ahumada, Eva Fernández-Muñoz, Samanta Giler, Mikel Valle, Glenn C. Telling, Mariví Geijó, Jesús R. Requena, Joaquín Castilla

Published in: Acta Neuropathologica Communications | Issue 1/2023

Abstract

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.

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Title: Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation
Authors: Hasier Eraña
Carlos M. Díaz-Domínguez
Jorge M. Charco
Enric Vidal
Ezequiel González-Miranda
Miguel A. Pérez-Castro
Patricia Piñeiro
Rafael López-Moreno
Cristina Sampedro-Torres-Quevedo
Leire Fernández-Veiga
Juan Tasis-Galarza
Nuria L. Lorenzo
Aileen Santini-Santiago
Melisa Lázaro
Sandra García-Martínez
Nuno Gonçalves-Anjo
Maitena San-Juan-Ansoleaga
Josu Galarza-Ahumada
Eva Fernández-Muñoz
Samanta Giler
Mikel Valle
Glenn C. Telling
Mariví Geijó
Jesús R. Requena
Joaquín Castilla
Publication date: 01-12-2023
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-023-01640-8

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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

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