Divergent prion strain evolution driven by PrP(C) expression level in transgenic mice

Prions induce a fatal neurodegenerative disease in infected host brain based on the refolding and aggregation of the host-encoded prion protein PrP(C) into PrP(Sc). Structurally distinct PrP(Sc) conformers can give rise to multiple prion strains. Constrained interactions between PrP(C) and different PrP(Sc) strains can in turn lead to certain PrP(Sc) (sub)populations being selected for cross-species transmission, or even produce mutation-like events. By contrast, prion strains are generally conserved when transmitted within the same species, or to transgenic mice expressing homologous PrP(C). Here, we compare the strain properties of a representative sheep scrapie isolate transmitted to a panel of transgenic mouse lines expressing varying levels of homologous PrP(C). While breeding true in mice expressing PrP(C) at near physiological levels, scrapie prions evolve consistently towards different strain components in mice beyond a certain threshold of PrP(C) overexpression. Our results support the view that PrP(C) gene dosage can influence prion evolution on homotypic transmission.