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Prion replication results from the autocatalytic templated assisted conversion of the host-encoded prion protein PrP C into misfolded, polydisperse PrP Sc conformers. Structurally distinct PrP Sc conformers can give rise to multiple prion strains. Within and between prion strains, the biological activity (replicative efficacy and specific infectivity) of PrP Sc assemblies is size dependent and thus reflects an intrinsic structural heterogeneity. The contribution of such PrP Sc heterogeneity across species prion adaptation, which is believed to be based on fit adjustment between PrP Sc template(s) and host PrP C , has not been explored. To define the structural-to-fitness PrP Sc landscape, we measured the relative capacity of size-fractionated PrP Sc assemblies from different prion strains to cross mounting species barriers in transgenic mice expressing foreign PrP C . In the absence of a transmission barrier, the relative efficacy of the isolated PrP Sc 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 PrP Sc 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 PrP Sc 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 PrP Sc 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 PrP Sc heterogeneity within prion population.

Among the ever-growing number of self-replicating proteins involved in neurodegenerative diseases, the prion protein PrP remains the most infamous for its central role in transmissible spongiform encephalopathies (TSEs). In these diseases, pathogenic prions propagate through a seeding mechanism, where normal PrP C molecules are converted into abnormally folded scrapie isoforms termed PrP Sc . Since its discovery over 30 years ago, much advance has contributed to define the host-encoded cellular prion protein PrP C as a critical relay of prion-induced neuronal cell demise. A current consensual view is that the conversion of PrP C into PrP Sc in neuronal cells diverts the former from its normal function with subsequent molecular alterations affecting synaptic plasticity. Here, we report that prion infection is associated with reduced expression of key effectors of the Notch pathway in vitro and in vivo, recapitulating changes fostered by the absence of PrP C . We further show that both prion infection and PrP C depletion promote drastic alterations in the expression of a defined set of Eph receptors and their ephrin ligands, which represent important players in synaptic function. Our data indicate that defects in the Notch and Eph axes can be mitigated in response to histone deacetylase inhibition in PrP C -depleted as well as prion-infected cells. We thus conclude that infectious prions cause a loss-of-function phenotype with respect to Notch and Eph signaling and that these alterations are sustained by epigenetic mechanisms.