Virologie Immunologie Moléculaires (VIM), INRA, Université Paris-Saclay, 78350 Jouy-en-Josas, France.
Génétique Animale et Biologie Intégrative (GABI), INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France.
Nat Commun. 2017 Jan 23;8:14170. doi: 10.1038/ncomms14170.
Prions induce a fatal neurodegenerative disease in infected host brain based on the refolding and aggregation of the host-encoded prion protein PrP into PrP. Structurally distinct PrP conformers can give rise to multiple prion strains. Constrained interactions between PrP and different PrP strains can in turn lead to certain PrP (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. 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. While breeding true in mice expressing PrP at near physiological levels, scrapie prions evolve consistently towards different strain components in mice beyond a certain threshold of PrP overexpression. Our results support the view that PrP gene dosage can influence prion evolution on homotypic transmission.
朊病毒基于宿主编码的朊病毒蛋白 PrP 的重折叠和聚集诱导感染宿主大脑中的致命神经退行性疾病。结构不同的 PrP 构象体可以产生多种朊病毒株。PrP 与不同朊病毒株之间的受限相互作用反过来可以导致某些 PrP（亚）群体被选择用于跨物种传播，甚至产生类似突变的事件。相比之下，当在同种内或在表达同源 PrP 的转基因小鼠中传播时，朊病毒株通常是保守的。在这里，我们比较了一种代表性绵羊瘙痒病分离株的株特性，该分离株传播到表达不同水平同源 PrP 的一组转基因小鼠系。虽然在表达接近生理水平的 PrP 的小鼠中表现出繁殖真实性，但在超过一定的 PrP 过表达阈值后，瘙痒病朊病毒在某些转基因小鼠中会持续朝着不同的株成分进化。我们的结果支持这样一种观点，即 PrP 基因剂量可以影响同种传播中的朊病毒进化。
