The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases1. Tau assemblies seem to spread through specific neural networks in each disease2, with short filaments having the greatest seeding activity3. The abundance of tau inclusions strongly correlates with disease symptoms4. Six tau isoforms are expressed in the normal adult human brain—three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau)1. In various diseases, tau filaments can be composed of either 3R or 4R tau, or of both. Tau filaments have distinct cellular and neuroanatomical distributions5, with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations6,7. Such conformers may give rise to different neuropathological phenotypes8,9, reminiscent of prion strains10. However, the underlying structures are not known. Using electron cryo-microscopy, we recently reported the structures of tau filaments from patients with Alzheimer’s disease, which contain both 3R and 4R tau11. Here we determine the structures of tau filaments from patients with Pick’s disease, a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues Lys254–Phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer’s disease, establishing the existence of conformers of assembled tau. The observed tau fold in the filaments of patients with Pick’s disease explains the selective incorporation of 3R tau in Pick bodies, and the differences in phosphorylation relative to the tau filaments of Alzheimer’s disease. Our findings show how tau can adopt distinct folds in the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers.The structures of tau filaments from patients with the neurodegenerative disorder Pick’s disease show that the filament fold is different from that of the tau filaments found in Alzheimer’s disease.

中文翻译：

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皮克病的细丝结构揭示了一种新的 tau 蛋白折叠

tau 蛋白有序组装成异常丝状包涵体是许多人类神经退行性疾病的基础。Tau 组件似乎通过每种疾病的特定神经网络传播2，短丝具有最大的播种活性3。tau 包裹体的丰度与疾病症状密切相关。六种 tau 亚型在正常成人大脑中表达——三种亚型分别具有四个微管结合重复 (4R tau) 和三个缺乏第二个重复的亚型 (3R tau)1。在各种疾病中，tau 丝可以由 3R 或 4R tau 或两者组成。Tau 细丝具有不同的细胞和神经解剖分布 5，形态和生化差异表明它们可能能够采用疾病特异性分子构象 6,7。这种构象异构体可能会产生不同的神经病理学表型 8、9，让人联想到朊病毒株 10。然而，底层结构是未知的。使用电子冷冻显微镜，我们最近报道了阿尔茨海默病患者的 tau 丝结构，其中包含 3R 和 4R tau11。在这里，我们确定了皮克病患者的 tau 丝结构，皮克病是一种以额颞叶痴呆为特征的神经退行性疾病。细丝由 3R tau 的残基 Lys254–Phe378 组成，它们的折叠方式与阿尔茨海默病中的 tau 细丝不同，从而确定了组装 tau 构象异构体的存在。在皮克病患者的细丝中观察到的 tau 折叠解释了 3R tau 在皮克体中的选择性掺入，以及与阿尔茨海默病的 tau 丝相关的磷酸化差异。我们的研究结果表明 tau 在不同疾病中如何在人脑中采用不同的折叠，这是了解分子构象异构体形成和传播的重要步骤。神经退行性疾病皮克病患者的 tau 细丝结构表明细丝折叠是不同的来自阿尔茨海默病中发现的 tau 细丝。