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Mixtures of prion substrains in natural scrapie cases revealed by ovinised murine models.

ABSTRACT: Phenotypic variability in prion diseases, such as scrapie, is associated to the existence of prion strains, which are different pathogenic prion protein (PrP^Sc) conformations with distinct pathobiological properties. To faithfully study scrapie strain variability in natural sheep isolates, transgenic mice expressing sheep cellular prion protein (PrP^C) are used. In this study, we used two of such models to bioassay 20 scrapie isolates from the Spain-France-Andorra transboundary territory. Animals were intracerebrally inoculated and survival periods, proteinase K-resistant PrP (PrP^res) banding patterns, lesion profiles and PrP^Sc distribution were studied. Inocula showed a remarkable homogeneity on banding patterns, all of them but one showing 19-kDa PrP^res. However, a number of isolates caused accumulation of 21-kDa PrP^res in TgShp XI. A different subgroup of isolates caused long survival periods and presence of 21-kDa PrP^res in Tg338 mice. It seemed that one major 19-kDa prion isoform and two distinct 21-kDa variants coexisted in source inocula, and that they could be separated by bioassay in each transgenic model. The reason why each model favours a specific component of the mixture is unknown, although PrP^C expression level may play a role. Our results indicate that coinfection with more than one substrain is more frequent than infection with a single component.

SUBMITTER: Barrio T

PROVIDER: S-EPMC7081250 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Mixtures of prion substrains in natural scrapie cases revealed by ovinised murine models.

Barrio Tomás T Filali Hicham H Otero Alicia A Sheleby-Elías Jessica J Marín Belén B Vidal Enric E Béringue Vincent V Torres Juan María JM Groschup Martin M Andréoletti Olivier O Badiola Juan José JJ Bolea Rosa R

Scientific reports 20200319 1

Phenotypic variability in prion diseases, such as scrapie, is associated to the existence of prion strains, which are different pathogenic prion protein (PrP<sup>Sc</sup>) conformations with distinct pathobiological properties. To faithfully study scrapie strain variability in natural sheep isolates, transgenic mice expressing sheep cellular prion protein (PrP<sup>C</sup>) are used. In this study, we used two of such models to bioassay 20 scrapie isolates from the Spain-France-Andorra transbound ...[more]

PMID: 32193445

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Project description:It is widely known that prion strains can mutate in response to modification of the replication environment and we have recently reported that prion mutations can occur in vitro during amplification of vole-adapted prions by Protein Misfolding Cyclic Amplification on bank vole substrate (bvPMCA). Here we exploited the high efficiency of prion replication by bvPMCA to study the in vitro propagation of natural scrapie isolates. Although in vitro vole-adapted PrPSc conformers were usually similar to the sheep counterpart, we repeatedly isolated a PrPSc mutant exclusively when starting from extremely diluted seeds of a single sheep isolate. The mutant and faithful PrPSc conformers showed to be efficiently autocatalytic in vitro and were characterized by different PrP protease resistant cores, spanning aa ?155-231 and ?80-231 respectively, and by different conformational stabilities. The two conformers could thus be seen as different bona fide PrPSc types, putatively accounting for prion populations with different biological properties. Indeed, once inoculated in bank vole the faithful conformer was competent for in vivo replication while the mutant was unable to infect voles, de facto behaving like a defective prion mutant. Overall, our findings confirm that prions can adapt and evolve in the new replication environments and that the starting population size can affect their evolutionary landscape, at least in vitro. Furthermore, we report the first example of "authentic" defective prion mutant, composed of brain-derived PrPC and originating from a natural scrapie isolate. Our results clearly indicate that the defective mutant lacks of some structural characteristics, that presumably involve the central region ?90-155, critical for infectivity but not for in vitro replication. Finally, we propose a molecular mechanism able to account for the discordant in vitro and in vivo behavior, suggesting possible new paths for investigating the molecular bases of prion infectivity.

Dataset Information

Mixtures of prion substrains in natural scrapie cases revealed by ovinised murine models.

Publications

Mixtures of prion substrains in natural scrapie cases revealed by ovinised murine models.

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