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Crossing Species Barriers Relies on Structurally Distinct Prion Assemblies and Their Complementation

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Abstract

Prion replication results from the autocatalytic templated assisted conversion of the host-encoded prion protein PrPC into misfolded, polydisperse PrPSc conformers. Structurally distinct PrPSc conformers can give rise to multiple prion strains. Within and between prion strains, the biological activity (replicative efficacy and specific infectivity) of PrPSc assemblies is size dependent and thus reflects an intrinsic structural heterogeneity. The contribution of such PrPSc heterogeneity across species prion adaptation, which is believed to be based on fit adjustment between PrPSc template(s) and host PrPC, has not been explored. To define the structural-to-fitness PrPSc landscape, we measured the relative capacity of size-fractionated PrPSc assemblies from different prion strains to cross mounting species barriers in transgenic mice expressing foreign PrPC. In the absence of a transmission barrier, the relative efficacy of the isolated PrPSc assemblies to induce the disease is like the efficacy observed in the homotypic context. However, in the presence of a transmission barrier, size fractionation overtly delays and even abrogates prion pathogenesis in both the brain and spleen tissues, independently of the infectivity load of the isolated assemblies. Altering by serial dilution PrPSc assembly content of non-fractionated inocula aberrantly reduces their specific infectivity, solely in the presence of a transmission barrier. This suggests that synergy between structurally distinct PrPSc assemblies in the inoculum is requested for crossing the species barrier. Our data support a mechanism whereby overcoming prion species barrier requires complementation between structurally distinct PrPSc assemblies. This work provides key insight into the “quasispecies” concept applied to prions, which would not necessarily rely on prion substrains as constituent but on structural PrPSc heterogeneity within prion population.

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Data Availability

All data supporting our findings are presented in the main paper and additional files.

Abbreviations

Bov:

bovine

BSE:

bovine spongiform encephalopathy

CJD:

Creutzfeldt-Jakob disease

Ha:

hamster

Ov:

ovine

PrP:

prion protein

PK:

proteinase K

PrPres :

proteinase K resistant PrPSc

PrPSc :

pathological/abnormal form of the prion protein

suPrP:

PrP elementary brick

SV:

sedimentation velocity

tg:

transgenic

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Acknowledgments

We thank the staff of Infectiology of fishes and rodent facilities (INRAE, Jouy-en-Josas, France; doi:https://doi.org/10.15454/1.5572427140471238E12) for animal care and Dr. Benjamin Dehay for critical reading of the manuscript.

Funding

This work was funded by the Fondation pour la Recherche Médicale (Equipe FRM DEQ20150331689), the European Research Council (ERC Starting Grant SKIPPERAD, number 306321), and the Ile de France region (DIM MALINF).

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Author notes

  1. Florent Laferrière

    Present address: Institute of Neurodegenerative Diseases, CNRS UMR5293, University of Bordeaux, Bordeaux, France

  2. Angélique Igel-Egalon, Florent Laferrière and Philippe Tixador contributed equally to this work.

Authors and Affiliations

  1. Université Paris-Saclay, INRAE, UVSQ, VIM, 78350, Jouy-en-Josas, France

    Angélique Igel-Egalon, Florent Laferrière, Philippe Tixador, Mohammed Moudjou, Laetitia Herzog, Fabienne Reine, Hubert Laude, Human Rezaei & Vincent Béringue

  2. Centro de Investigación en Sanidad Animal (CISA-INIA), Valdeolmos, Madrid, Spain

    Juan Maria Torres

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Contributions

Conceptualization, AIE, FL, PT, MM, HL, HR, and VB. Data curation and analysis, AIE, FL, PT, MM, LH, FR, JMT, HL, HR, and VB. Resources, HL, JMT, HR, and VB. Writing – original draft, AIE, HR, and VB. Writing – review and editing, AIE, HR, and VB. Visualization, AIE, HR, and VB. Supervision, VB. Funding acquisition, HR and VB. All authors read and approved the final manuscript.

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Correspondence to Human Rezaei or Vincent Béringue.

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All the experiments involving animals were carried out in strict accordance with EU directive 2010/63 and were approved by INRA local ethics committee (Comethea; permit numbers 12-034 and 15-056).

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Igel-Egalon, A., Laferrière, F., Tixador, P. et al. Crossing Species Barriers Relies on Structurally Distinct Prion Assemblies and Their Complementation. Mol Neurobiol 57, 2572–2587 (2020). https://doi.org/10.1007/s12035-020-01897-3

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