小柯机器人

英国MRC分子生物学实验室Sjors H. W. Scheres等研究人员合作发现，疾病特异性tau细丝通过多态中间体来组装。相关论文于2023年11月29日在线发表在《自然》杂志上。

研究人员使用时间分辨冷冻电镜研究了重组截短tau（氨基酸残基297-391），体外组装成阿尔茨海默病成对螺旋状丝或慢性创伤性脑病丝的过程。研究人员报告了共用的第一中间淀粉样蛋白丝的形成，其有序核心包括残基302-316。核磁共振表明，这些残基在tau单体中具有类似β-strand的刚性构象。在稍后的时间点，第一个中间淀粉样蛋白消失，研究人员观察到许多不同的中间淀粉样蛋白丝，其结构取决于反应条件。

在两个组装反应结束时，大多数中间淀粉样蛋白消失，而具有与人脑中的淀粉样蛋白相同的有序核心的丝状物依然存在。这些研究结果从结构上揭示了淀粉样蛋白组装的初级和次级成核过程，对新疗法的设计具有重要意义。

据了解，淀粉样蛋白丝组装过程中的中间体被认为在神经退行性疾病中起着核心作用，并可能成为治疗干预的重要目标。然而，有关中间体的结构信息一直很少，淀粉样蛋白组装的分子机制在很大程度上仍不为人所知。

附：英文原文

Title: Disease-specific tau filaments assemble via polymorphic intermediates

Author: Lvestam, Sofia, Li, David, Wagstaff, Jane L., Kotecha, Abhay, Kimanius, Dari, McLaughlin, Stephen H., Murzin, Alexey G., Freund, Stefan M. V., Goedert, Michel, Scheres, Sjors H. W.

Issue&Volume: 2023-11-29

Abstract: Intermediate species in the assembly of amyloid filaments are believed to play a central role in neurodegenerative diseases and may constitute important targets for therapeutic intervention1,2. However, structural information about intermediate species has been scarce and the molecular mechanisms by which amyloids assemble remain largely unknown. Here we use time-resolved cryogenic electron microscopy to study the in vitro assembly of recombinant truncated tau (amino acid residues 297–391) into paired helical filaments of Alzheimer’s disease or into filaments of chronic traumatic encephalopathy3. We report the formation of a shared first intermediate amyloid filament, with an ordered core comprising residues 302–316. Nuclear magnetic resonance indicates that the same residues adopt rigid, β-strand-like conformations in monomeric tau. At later time points, the first intermediate amyloid disappears and we observe many different intermediate amyloid filaments, with structures that depend on the reaction conditions. At the end of both assembly reactions, most intermediate amyloids disappear and filaments with the same ordered cores as those from human brains remain. Our results provide structural insights into the processes of primary and secondary nucleation of amyloid assembly, with implications for the design of new therapies.

DOI: 10.1038/s41586-023-06788-w

Source: https://www.nature.com/articles/s41586-023-06788-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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