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.