Prions from Sporadic Creutzfeldt-Jakob Disease Patients Propagate as Strain Mixtures

ABSTRACT Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently classified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K-digested abnormal prion protein (PrPres) isoform identified by Western blotting (type 1 or type 2). Converging evidence...

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Autores principales: Hervé Cassard, Alvina Huor, Juan-Carlos Espinosa, Jean-Yves Douet, Severine Lugan, Naima Aron, Didier Vilette, Marie-Bernadette Delisle, Alba Marín-Moreno, Patrice Peran, Vincent Beringue, Juan Maria Torres, James W. Ironside, Olivier Andreoletti
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Publicado: American Society for Microbiology 2020
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spelling oai:doaj.org-article:d418ac5dd0e847f99e8b5b2eafd0fb342021-11-15T15:56:46ZPrions from Sporadic Creutzfeldt-Jakob Disease Patients Propagate as Strain Mixtures10.1128/mBio.00393-202150-7511https://doaj.org/article/d418ac5dd0e847f99e8b5b2eafd0fb342020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00393-20https://doaj.org/toc/2150-7511ABSTRACT Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently classified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K-digested abnormal prion protein (PrPres) isoform identified by Western blotting (type 1 or type 2). Converging evidence led to the view that MM/MV1, VV/MV2, and VV1 and MM2 sCJD cases are caused by distinct prion strains. However, in a significant proportion of sCJD patients, both type 1 and type 2 PrPres were reported to accumulate in the brain, which raised questions about the diversity of sCJD prion strains and the coexistence of two prion strains in the same patient. In this study, a panel of sCJD brain isolates (n = 29) that displayed either a single or mixed type 1/type 2 PrPres were transmitted into human-PrP-expressing mice (tgHu). These bioassays demonstrated that two distinct prion strains (M1CJD and V2CJD) were associated with the development of sCJD in MM1/MV1 and VV2/MV2 patients. However, in about 35% of the investigated VV and MV cases, transmission results were consistent with the presence of both M1CJD and V2CJD strains, including in patients who displayed a “pure” type 1 or type 2 PrPres. The use of a highly sensitive prion in vitro amplification technique that specifically probes the V2CJD strain revealed the presence of the V2CJD prion in more than 80% of the investigated isolates, including isolates that propagated as a pure M1CJD strain in tgHu. These results demonstrate that at least two sCJD prion strains can be present in a single patient. IMPORTANCE sCJD occurrence is currently assumed to result from spontaneous and stochastic formation of a misfolded PrP nucleus in the brains of affected patients. This original nucleus then recruits and converts nascent PrPC into PrPSc, leading to the propagation of prions in the patient’s brain. Our study demonstrates the coexistence of two prion strains in the brains of a majority of the 23 sCJD patients investigated. The relative proportion of these sCJD strains varied both between patients and between brain areas in a single patient. These findings strongly support the view that the replication of an sCJD prion strain in the brain of a patient can result in the propagation of different prion strain subpopulations. Beyond its conceptual importance for our understanding of prion strain properties and evolution, the sCJD strain mixture phenomenon and its frequency among patients have important implications for the development of therapeutic strategies for prion diseases.Hervé CassardAlvina HuorJuan-Carlos EspinosaJean-Yves DouetSeverine LuganNaima AronDidier ViletteMarie-Bernadette DelisleAlba Marín-MorenoPatrice PeranVincent BeringueJuan Maria TorresJames W. IronsideOlivier AndreolettiAmerican Society for Microbiologyarticleprionsporadic Creutzfeldt-Jakob diseasestrain diversityevolutiondiversityprionsMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution DOAJ
collection DOAJ
language EN
topic prion
sporadic Creutzfeldt-Jakob disease
strain diversity
evolution
diversity
prions
Microbiology
QR1-502
spellingShingle prion
sporadic Creutzfeldt-Jakob disease
strain diversity
evolution
diversity
prions
Microbiology
QR1-502
Hervé Cassard
Alvina Huor
Juan-Carlos Espinosa
Jean-Yves Douet
Severine Lugan
Naima Aron
Didier Vilette
Marie-Bernadette Delisle
Alba Marín-Moreno
Patrice Peran
Vincent Beringue
Juan Maria Torres
James W. Ironside
Olivier Andreoletti
Prions from Sporadic Creutzfeldt-Jakob Disease Patients Propagate as Strain Mixtures
description ABSTRACT Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently classified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K-digested abnormal prion protein (PrPres) isoform identified by Western blotting (type 1 or type 2). Converging evidence led to the view that MM/MV1, VV/MV2, and VV1 and MM2 sCJD cases are caused by distinct prion strains. However, in a significant proportion of sCJD patients, both type 1 and type 2 PrPres were reported to accumulate in the brain, which raised questions about the diversity of sCJD prion strains and the coexistence of two prion strains in the same patient. In this study, a panel of sCJD brain isolates (n = 29) that displayed either a single or mixed type 1/type 2 PrPres were transmitted into human-PrP-expressing mice (tgHu). These bioassays demonstrated that two distinct prion strains (M1CJD and V2CJD) were associated with the development of sCJD in MM1/MV1 and VV2/MV2 patients. However, in about 35% of the investigated VV and MV cases, transmission results were consistent with the presence of both M1CJD and V2CJD strains, including in patients who displayed a “pure” type 1 or type 2 PrPres. The use of a highly sensitive prion in vitro amplification technique that specifically probes the V2CJD strain revealed the presence of the V2CJD prion in more than 80% of the investigated isolates, including isolates that propagated as a pure M1CJD strain in tgHu. These results demonstrate that at least two sCJD prion strains can be present in a single patient. IMPORTANCE sCJD occurrence is currently assumed to result from spontaneous and stochastic formation of a misfolded PrP nucleus in the brains of affected patients. This original nucleus then recruits and converts nascent PrPC into PrPSc, leading to the propagation of prions in the patient’s brain. Our study demonstrates the coexistence of two prion strains in the brains of a majority of the 23 sCJD patients investigated. The relative proportion of these sCJD strains varied both between patients and between brain areas in a single patient. These findings strongly support the view that the replication of an sCJD prion strain in the brain of a patient can result in the propagation of different prion strain subpopulations. Beyond its conceptual importance for our understanding of prion strain properties and evolution, the sCJD strain mixture phenomenon and its frequency among patients have important implications for the development of therapeutic strategies for prion diseases.
format article
author Hervé Cassard
Alvina Huor
Juan-Carlos Espinosa
Jean-Yves Douet
Severine Lugan
Naima Aron
Didier Vilette
Marie-Bernadette Delisle
Alba Marín-Moreno
Patrice Peran
Vincent Beringue
Juan Maria Torres
James W. Ironside
Olivier Andreoletti
author_facet Hervé Cassard
Alvina Huor
Juan-Carlos Espinosa
Jean-Yves Douet
Severine Lugan
Naima Aron
Didier Vilette
Marie-Bernadette Delisle
Alba Marín-Moreno
Patrice Peran
Vincent Beringue
Juan Maria Torres
James W. Ironside
Olivier Andreoletti
author_sort Hervé Cassard
title Prions from Sporadic Creutzfeldt-Jakob Disease Patients Propagate as Strain Mixtures
title_short Prions from Sporadic Creutzfeldt-Jakob Disease Patients Propagate as Strain Mixtures
title_full Prions from Sporadic Creutzfeldt-Jakob Disease Patients Propagate as Strain Mixtures
title_fullStr Prions from Sporadic Creutzfeldt-Jakob Disease Patients Propagate as Strain Mixtures
title_full_unstemmed Prions from Sporadic Creutzfeldt-Jakob Disease Patients Propagate as Strain Mixtures
title_sort prions from sporadic creutzfeldt-jakob disease patients propagate as strain mixtures
publisher American Society for Microbiology
publishDate 2020
url https://doaj.org/article/d418ac5dd0e847f99e8b5b2eafd0fb34
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