Intracellular tau fragment droplets serve as seeds for tau fibrils

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Structure Pub Date : 2024-07-19 DOI:10.1016/j.str.2024.06.018

引用次数: 0

Abstract

Intracellular tau aggregation requires a local protein concentration increase, referred to as “droplets”. However, the cellular mechanism for droplet formation is poorly understood. Here, we expressed OptoTau, a P301L mutant tau fused with CRY2olig, a light-sensitive protein that can form homo-oligomers. Under blue light exposure, OptoTau increased tau phosphorylation and was sequestered in aggresomes. Suppressing aggresome formation by nocodazole formed tau granular clusters in the cytoplasm. The granular clusters disappeared by discontinuing blue light exposure or 1,6-hexanediol treatment suggesting that intracellular tau droplet formation requires microtubule collapse. Expressing OptoTau-ΔN, a species of N-terminal cleaved tau observed in the Alzheimer’s disease brain, formed 1,6-hexanediol and detergent-resistant tau clusters in the cytoplasm with blue light stimulation. These intracellular stable tau clusters acted as a seed for tau fibrils in vitro. These results suggest that tau droplet formation and N-terminal cleavage are necessary for neurofibrillary tangles formation in neurodegenerative diseases.

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细胞内的 tau 片段小滴是 tau 纤维的种子

细胞内 tau 的聚集需要局部蛋白质浓度的增加，即所谓的 "液滴"。然而，人们对液滴形成的细胞机制知之甚少。在这里，我们表达了OptoTau，一种与CRY2olig融合的P301L突变体tau，CRY2olig是一种对光敏感的蛋白质，可以形成同源异构体。在蓝光照射下，OptoTau增加了tau的磷酸化，并固着在凝集体中。用nocodazole抑制凝集体的形成会在细胞质中形成tau颗粒簇。停止蓝光照射或1,6-己二醇处理后，颗粒簇消失，这表明细胞内tau小滴的形成需要微管塌缩。表达 OptoTau-ΔN（一种在阿尔茨海默病大脑中观察到的 N 端裂解 tau）的细胞在蓝光刺激下会在细胞质中形成抗 1,6- 己二醇和去垢剂的 tau 簇。这些细胞内稳定的 tau 簇在体外可作为 tau 纤维的种子。这些结果表明，在神经退行性疾病中，tau小滴的形成和N端裂解是神经纤维缠结形成的必要条件。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.