Medical Research Council Prion Unit at University College London (UCL), UCL Institute of Prion Diseases, London W1W 7FF, United Kingdom.
Medical Research Council Prion Unit at University College London (UCL), UCL Institute of Prion Diseases, London W1W 7FF, United Kingdom
Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23815-23822. doi: 10.1073/pnas.2007406117. Epub 2020 Sep 8.
Prions are infectious agents which cause rapidly lethal neurodegenerative diseases in humans and animals following long, clinically silent incubation periods. They are composed of multichain assemblies of misfolded cellular prion protein. While it has long been assumed that prions are themselves neurotoxic, recent development of methods to obtain exceptionally pure prions from mouse brain with maintained strain characteristics, and in which defined structures-paired rod-like double helical fibers-can be definitively correlated with infectivity, allowed a direct test of this assertion. Here we report that while brain homogenates from symptomatic prion-infected mice are highly toxic to cultured neurons, exceptionally pure intact high-titer infectious prions are not directly neurotoxic. We further show that treatment of brain homogenates from prion-infected mice with sodium lauroylsarcosine destroys toxicity without diminishing infectivity. This is consistent with models in which prion propagation and toxicity can be mechanistically uncoupled.
朊病毒是传染性病原体，可导致人类和动物在长时间、临床无症状潜伏期后迅速发生致命的神经退行性疾病。它们由错误折叠的细胞朊病毒蛋白多链组装而成。虽然长期以来人们一直认为朊病毒本身具有神经毒性，但最近开发出了从具有维持的株特征的鼠脑中获得异常纯净的朊病毒的方法，并且其中定义的结构——配对的杆状双链螺旋纤维——可以与感染性明确相关，从而可以直接测试这一断言。在这里，我们报告说，虽然来自症状性朊病毒感染小鼠的脑匀浆对培养的神经元具有高度毒性，但异常纯净的完整高滴度传染性朊病毒本身并不直接具有神经毒性。我们进一步表明，用十二酰肌氨酸钠处理来自朊病毒感染小鼠的脑匀浆可在不降低感染性的情况下消除毒性。这与朊病毒传播和毒性可以在机制上分离的模型一致。
