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

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.

journal_name

Mol Neurobiol

journal_title

Molecular neurobiology

authors

Igel-Egalon A,Laferrière F,Tixador P,Moudjou M,Herzog L,Reine F,Torres JM,Laude H,Rezaei H,Béringue V

doi

10.1007/s12035-020-01897-3

subject

Has Abstract

pub_date

2020-06-01 00:00:00

pages

2572-2587

issue

eissn

0893-7648

issn

1559-1182

pii

10.1007/s12035-020-01897-3

journal_volume

pub_type

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