Divergent prion strain evolution driven by PrPC expression level in transgenic mice

Annick Le Dur (1) , Thanh Lan Lai-Thi (1) , Marie-George Stinnakre (2, 3, 4) , Aude Laisne (1) , Nathalie Chenais (2) , Sabine Rakotobe (1) , Bruno Passet (2) , Fabienne Reine (1) , Solange Soulier (2, 3, 4) , Laetitia Herzog (1) , Gaelle Tilly (2) , Human Rezaei (1) , Vincent Béringue (1) , Jean-Luc Vilotte (2) , Hubert Laude (1)

1 VIM (UR 0892) - Unité de recherche Virologie et Immunologie Moléculaires
2 GABI - Génétique Animale et Biologie Intégrative
3 AgroParisTech
4 Université Paris-Saclay

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.

Domaines: Sciences du Vivant [q-bio]

Annick Le Dur, Thanh Lan Lai-Thi, Marie-George Stinnakre, Aude Laisne, Nathalie Chenais, et al.. Divergent prion strain evolution driven by PrPC expression level in transgenic mice. Nature Communications, 2017, 8, pp.1-11. ⟨10.1038/ncomms14170⟩. ⟨hal-01605904⟩