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

Angélique Igel-Egalon, Florent Laferrière, Philippe Tixador, Mohammed Moudjou, Laetitia Herzog, Fabienne Reine, Juan Maria Torres, Hubert Laude, Human Rezaei, Vincent Béringue
Mol Neurobiol. 2020-04-01; 57(6): 2572-2587
DOI: 10.1007/s12035-020-01897-3

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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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