Understanding the key features of the spontaneous formation of bona fde prions through a novel methodology that enables their swift and consistent generation
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Author
Eraña, Hasier
Díaz‑Domínguez, Carlos M.
Charco, Jorge M.
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
Publication date
2023-09-07ISSN
2051-5960
Abstract
Among transmissible spongiform encephalopathies or prion diseases afecting humans, sporadic forms such as spo‑
radic 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 (PrPC) into the patho‑
genic isoform (PrPSc). 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 infre‑
quent and stochastic, hindering the systematic study of the phenomenon. In this study, we present the frst method
that consistently induces spontaneous misfolding of recombinant PrP into bona fde prions within hours, providing
unprecedented possibilities to investigate the mechanisms underlying sporadic prionopathies. By fne‑tuning the Pro‑
tein Misfolding Shaking Amplifcation 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 infuence of charged sur‑
faces in this process.
Document Type
Article
Document version
Published version
Language
English
Subject (CDU)
619 - Veterinary science
Pages
30
Publisher
BMC
Is part of
Acta Neuropathologica Communications
Citation
Eraña, Hasier, Carlos M. Díaz-Domínguez, Jorge M. Charco, Enric Vidal, Ezequiel González-Miranda, Miguel A. Pérez-Castro, Patricia Piñeiro, et al. 2023. “Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation“. Acta Neuropathologica Communications 11 (1): 145. doi:10.1186/s40478-023-01640-8.
Grant agreement number
MC/Programa Estatal para impulsar la investigación científico-técnica y su transferencia/PID2021-122201OB-C21/ES/ANALISIS DEL MALPLEGAMIENTO IN VITRO DE UNA DIVERSIDAD DE PROTEINAS DEL PRION PARA LA GENERACION DE NUEVAS ENTIDADES INFECCIOSAS Y DESARROLLO DE APROXIMACIONES TERAPEUTICAS/
MC/Programa Estatal para impulsar la investigación científico-técnica y su transferencia/PID2021-122201OB-C22/ES/DESARROLLO DE INNOVADORES MODELOS DE ENFERMEDADES PRIONICAS Y ESTUDIO DE LA PATOBIOLOGIA DE PRIONES SINTETICOS EN RATONES TRANSGENICOS Y HOSPEDADORES POCO COMUNES/ZOOPRION
MC/Programa Estatal de generación del conocimiento y fortalecimiento científico y tecnológico del sistema I+D+I y Programa Estatal de I+D+I orientada a los retos de la sociedad/PID2020-117465GB-I00/ES/ /
FEDER/ / /EU/ /
ISCIII/ /AC21_2-00024/ES/Biomarcadores prodrómicos en Insomnio Familiar Letal: Un estudio longitudinal en humanos y ratones/
MICINN/Programa Estatal para impulsar la investigación científico-técnica y su transferencia/CEX2021-001136-S/ES/ /
Program
Sanitat Animal
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