Abstract
Prions induce a fatal neurodegenerative disease in infected host brain based on the refolding and aggregation of the host-encoded prion protein PrPC into PrPSc. Structurally distinct PrPSc conformers can give rise to multiple prion strains. Constrained interactions between PrPC and different PrPSc strains can in turn lead to certain PrPSc (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 PrPC. 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 PrPC. While breeding true in mice expressing PrPC at near physiological levels, scrapie prions evolve consistently towards different strain components in mice beyond a certain threshold of PrPC overexpression. Our results support the view that PrPC gene dosage can influence prion evolution on homotypic transmission.
Highlights
Prions induce a fatal neurodegenerative disease in infected host brain based on the refolding and aggregation of the host-encoded prion protein PrPC into PrPSc
When subpassaging was performed using homogenates prepared from several brains, an agent with either LA21K fast or LA19K phenotype was propagated depending on whether mouse no. 9 was included in the pool or not (Fig. 1b)
In this study we provide experimental evidence that on homotypic transmission of a natural prion source to transgenic mice, different strains may be propagated depending on the PrPC gene dosage in the recipient line
Summary
Based mostly on PrP transgenic mouse models data[22], the conformational selection model[11,23] posits that the transmission barrier stringency depends on the degree of steric compatibility between PrPSc structure(s) present in the infecting prion and host PrPC conformational landscape. Homotypic transmissions (that is, when the host expresses the same PrP amino acid sequence as the infecting prion) generally result in apparent lack of transmission barrier and conservation of strain type[24,29,30,31]. We examined the outcome of prion homotypic transmissions by comparing the transmission pattern of sheep prion isolates on multiple lines of transgenic mice expressing varying levels of the VRQ allele of ovine PrP, associated with the highest susceptibility to scrapie[35]. Our findings reveal a new facet of the biology of prions, with both practical and theoretical implications
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