Mammalian prions are lethal transmissible pathogens that cause fatal neurodegenerative diseases in humans and animals. They consist of fibrils of misfolded, host-encoded prion protein (PrP) which propagate through templated protein polymerisation. Prion strains produce distinct clinicopathological phenotypes in the same host and appear to be encoded by distinct misfolded PrP conformations and assembly states. Despite fundamental advances in our understanding of prion biology, key knowledge gaps remain. These include precise delineation of prion replication mechanisms, detailed explanation of the molecular basis of prion strains and inter-species transmission barriers, and the structural definition of neurotoxic PrP species. Central to addressing these questions is the determination of prion structure. While high-resolution definition of ex vivo prion fibrils once seemed unlikely, recent advances in cryo-electron microscopy (cryo-EM) and computational methods for 3D reconstruction of amyloids have now made this possible. Recently, near-atomic resolution structures of highly infectious, ex vivo prion fibrils from hamster 263K and mouse RML prion strains were reported. The fibrils have a comparable parallel in-register intermolecular β-sheet (PIRIBS) architecture that now provides a structural foundation for understanding prion strain diversity in mammals. Here, we review these new findings and discuss directions for future research.

哺乳动物朊病毒是致命的可传播病原体，可导致人类和动物致命的神经退行性疾病。它们由错误折叠的原纤维组成，宿主编码的朊病毒蛋白 (PrP) 通过模板化蛋白质聚合进行繁殖。朊病毒菌株在同一宿主中产生不同的临床病理表型，并且似乎由不同的错误折叠 PrP 构象和组装状态编码。尽管我们对朊病毒生物学的理解取得了根本性进展，但关键的知识差距仍然存在。其中包括对朊病毒复制机制的精确描述、对朊病毒菌株和种间传播障碍的分子基础的详细解释，以及神经毒性 PrP 物种的结构定义。解决这些问题的核心是确定朊病毒结构。虽然离体朊病毒原纤维的高分辨率定义曾经似乎不太可能，但冷冻电子显微镜 (cryo-EM) 和淀粉样蛋白 3D 重建计算方法的最新进展现在使这成为可能。最近，报道了来自仓鼠 263K 和小鼠 RML 朊病毒株的高度传染性离体朊病毒原纤维的近原子分辨率结构。原纤维具有类似的平行登记分子间 β-折叠 (PIRIBS) 结构，现在为理解哺乳动物的朊病毒菌株多样性提供了结构基础。在这里，我们回顾了这些新发现并讨论了未来研究的方向。报道了来自仓鼠 263K 和小鼠 RML 朊病毒株的高度传染性离体朊病毒原纤维的近原子分辨率结构。原纤维具有类似的平行登记分子间 β-折叠 (PIRIBS) 结构，现在为理解哺乳动物的朊病毒菌株多样性提供了结构基础。在这里，我们回顾了这些新发现并讨论了未来研究的方向。报道了来自仓鼠 263K 和小鼠 RML 朊病毒株的高度传染性离体朊病毒原纤维的近原子分辨率结构。原纤维具有类似的平行登记分子间 β-折叠 (PIRIBS) 结构，现在为理解哺乳动物的朊病毒菌株多样性提供了结构基础。在这里，我们回顾了这些新发现并讨论了未来研究的方向。