The role of liquid-liquid phase separation in aggregation of the TDP-43 low-complexity domain
The role of liquid-liquid phase separation in aggregation of the TDP-43 low-complexity domain
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DOI：
10.1074/jbc.ra118.007222
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发表时间：
2019-04-19
影响因子：
4.8
通讯作者：
Surewicz, Witold K.
中科院分区：
文献类型：
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作者：
Babinchak, W. Michael;Haider, Raza;Surewicz, Witold K.
43 kDa的反式反应DNA结合蛋白（TDP-43）的病理性聚集与几种神经退行性疾病相关，包括ALS、额颞叶痴呆、慢性创伤性脑病和阿尔茨海默病。TDP-43聚集似乎在很大程度上是由其低复杂性结构域（LCD）驱动的，该结构域也具有进行液-液相分离（LLPS）的高倾向。然而，TDP-43 LCD病理性聚集的机制以及最重要的是聚集过程与LLPS之间的关系在很大程度上仍然未知。在这里，我们表明，淀粉样蛋白形成的液晶显示器是由静电斥力控制。我们还表明，液滴环境强烈加速LCD原纤化，其在LLPS条件下的聚集涉及几个不同的事件，最终在快速组装的纤维状聚集体，从成熟的液滴内发出。这些综合结果强烈表明，LLPS可能在病理性TDP-43聚集中发挥重要作用，有助于神经退行性疾病的发病机制。
Pathological aggregation of the transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with several neurodegenerative disorders, including ALS, frontotemporal dementia, chronic traumatic encephalopathy, and Alzheimer's disease. TDP-43 aggregation appears to be largely driven by its low-complexity domain (LCD), which also has a high propensity to undergo liquid-liquid phase separation (LLPS). However, the mechanism of TDP-43 LCD pathological aggregation and, most importantly, the relationship between the aggregation process and LLPS remains largely unknown. Here, we show that amyloid formation by the LCD is controlled by electrostatic repulsion. We also demonstrate that the liquid droplet environment strongly accelerates LCD fibrillation and that its aggregation under LLPS conditions involves several distinct events, culminating in rapid assembly of fibrillar aggregates that emanate from within mature liquid droplets. These combined results strongly suggest that LLPS may play a major role in pathological TDP-43 aggregation, contributing to pathogenesis in neurodegenerative diseases.