Cryo-EM structure of a natural prion: chronic wasting disease fibrils from deer

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Acta Neuropathologica Pub Date : 2024-10-24 DOI:10.1007/s00401-024-02813-y
Parvez Alam, Forrest Hoyt, Efrosini Artikis, Jakub Soukup, Andrew G. Hughson, Cindi L. Schwartz, Kent Barbian, Michael W. Miller, Brent Race, Byron Caughey
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Abstract

Chronic wasting disease (CWD) is a widely distributed prion disease of cervids with implications for wildlife conservation and also for human and livestock health. The structures of infectious prions that cause CWD and other natural prion diseases of mammalian hosts have been poorly understood. Here we report a 2.8 Å resolution cryogenic electron microscopy-based structure of CWD prion fibrils from the brain of a naturally infected white-tailed deer expressing the most common wild-type PrP sequence. Like recently solved rodent-adapted scrapie prion fibrils, our atomic model of CWD fibrils contains single stacks of PrP molecules forming parallel in-register intermolecular β-sheets and intervening loops comprising major N- and C-terminal lobes within the fibril cross-section. However, CWD fibrils from a natural cervid host differ markedly from the rodent structures in many other features, including a ~ 180° twist in the relative orientation of the lobes. This CWD structure suggests mechanisms underlying the apparent CWD transmission barrier to humans and should facilitate more rational approaches to the development of CWD vaccines and therapeutics.

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天然朊病毒的冷冻电子显微镜结构:来自鹿的慢性消耗性疾病纤维蛋白
慢性消耗性疾病(CWD)是一种广泛分布的颈鹿朊病毒疾病,对野生动物保护以及人类和牲畜健康都有影响。人们对导致 CWD 和哺乳动物宿主其他天然朊病毒疾病的传染性朊病毒的结构知之甚少。在此,我们报告了一种基于 2.8 Å 分辨率低温电子显微镜的 CWD 朊病毒纤维结构,该结构来自表达最常见野生型 PrP 序列的自然感染白尾鹿的大脑。与最近解决的啮齿动物适应性豚鼠瘙痒症朊病毒纤维一样,我们的CWD纤维原子模型也包含单堆PrP分子,这些分子形成了平行的套内分子间β片和由纤维横截面内主要N端和C端叶组成的间隔环。然而,来自天然鹿宿主的 CWD 纤维在许多其他特征上与啮齿类动物的结构明显不同,其中包括裂片相对方向的约 180° 扭转。这种 CWD 结构揭示了 CWD 向人类传播的明显障碍的内在机制,并有助于采用更合理的方法来开发 CWD 疫苗和疗法。
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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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