A Protein Misfolding Shaking Amplification-based method for the spontaneous generation of hundreds of bona fide prions
Eraña, Hasier (ATLAS Molecular Pharma S. L)
Sampedro-Torres-Quevedo, Cristina (Basque Research and Technology Alliance)
Charco, Jorge M. (ATLAS Molecular Pharma S. L)
Díaz-Domínguez, Carlos M. (Instituto de Salut Carlos III. Centro de Investigación Biomédica en Red de Enfermedades infecciosas)
Peccati, Francesca (Basque Research and Technology Alliance)
San-Juan-Ansoleaga, Maitena (Basque Research and Technology Alliance)
Vidal Barba, Enric (Unitat mixta d'investigació IRTA-UAB en Sanitat Animal. Centre de Recerca en Sanitat Animal)
Gonçalves-Anjo, Nuno (Basque Research and Technology Alliance)
Pérez-Castro, Miguel A. (Basque Research and Technology Alliance)
González-Miranda, Ezequiel (Basque Research and Technology Alliance)
Piñeiro, Patricia (Basque Research and Technology Alliance)
Fernández-Veiga, Leire (Basque Research and Technology Alliance)
Galarza-Ahumada, Josu (Basque Research and Technology Alliance)
Fernández-Muñoz, Eva (Basque Research and Technology Alliance)
Pérez de Nanclares, Guiomar (Hospital Universitario de Araba Molecular (Epi)Genetics Laboratory)
Telling, Glenn (Colorado State University. Prion Research Center)
Geijo, Maria V (NEIKER-Basque Institute for Agricultural Research and Development)
Jiménez-Osés, Gonzalo (Basque Foundation for Science)
Castilla, Joaquín (Basque Foundation for Science)

Date:	2024
Abstract:	Prion diseases are a group of rapidly progressing neurodegenerative disorders caused by the misfolding of the endogenous prion protein (PrP C) into a pathogenic form (PrP Sc). This process, despite being the central event underlying these disorders, remains largely unknown at a molecular level, precluding the prediction of new potential outbreaks or interspecies transmission incidents. In this work, we present a method to generate bona fide recombinant prions de novo, allowing a comprehensive analysis of protein misfolding across a wide range of prion proteins from mammalian species. We study more than 380 different prion proteins from mammals and classify them according to their spontaneous misfolding propensity and their conformational variability. This study aims to address fundamental questions in the prion research field such as defining infectivity determinants, interspecies transmission barriers or the structural influence of specific amino acids and provide invaluable information for future diagnosis and therapy applications. To study neurodegenerative prion diseases, a method (PMSA) for generating prions spontaneously is presented. Applied to 380+ different prion proteins, their tendency to become pathogenic was ranked, illuminating their formation process.
Grants:	Ministerio de Economía y Competitividad PID2021-122201OB-C21 Ministerio de Economía y Competitividad PID2021-1222010B-C22 Ministerio de Economía y Competitividad PID2021-125946OB-I00 Agencia Estatal de Investigación IJC2020-045506-I
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Neurodegeneration ; Diseases of the nervous system ; Encephalopathy ; Prions ; Protein aggregation
Published in:	Nature communications, Vol. 15 (march 2024) , ISSN 2041-1723

DOI: 10.1038/s41467-024-46360-2
PMID: 38459071

14 p, 2.1 MB

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