Complementation between pathological prion protein subassemblies to cross existing species barriers

Abstract

Backgroundprion 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. Methodsto 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. Resultsin the absence of a transmission barrier, the relative efficacy of the isolated PrPSc assemblies to induce the disease is superimposable to 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 neural and extraneural, prion-permissive tissues, for reason independent of the infectivity load of the isolated assemblies. This suggests that a synergy between structurally distinct PrPSc assemblies in the inoculum is requested for crossing the species barrier. We further strengthen this hypothesis by showing that altering, by serial dilution, PrPSc assemblies content of unfractionated inocula reduce their specific infectivity in an aberrant manner, solely in the presence of a transmission barrier. Conclusionsour data support a mechanism whereby overcoming prion species barrier requires complementation between structurally distinct PrPSc assemblies. This work provides key insight into the "quasi-species" concept applied to prions, which would not necessarily rely on prion sub-strains as constituent but on structural PrPSc heterogeneity within prion population.