Tau is a microtubule-associated protein that plays a major role in Alzheimer's disease (AD) and other tauopathies. Recent reports indicate that, in the presence of crowding agents, tau can undergo liquid-liquid phase separation (LLPS), forming highly dynamic liquid droplets. Here, using recombinantly expressed proteins, turbidimetry, fluorescence microscopy imaging, and fluorescence recovery after photobleaching (FRAP) assays, we show that the divalent transition metal zinc strongly promotes this process, shifting the equilibrium phase boundary to lower protein or crowding agent concentrations. We observed no tau LLPS-promoting effect for any other divalent transition metal ions tested, including Mn2+, Fe2+, Co2+, Ni2+, and Cu2+ We also demonstrate that multiple zinc-binding sites on tau are involved in the LLPS-promoting effect and provide insights into the mechanism of this process. Zinc concentration is highly elevated in AD brains, and this metal ion is believed to be an important player in the pathogenesis of this disease. Thus, the present findings bring a new dimension to understanding the relationship between zinc homeostasis and the pathogenic process in AD and related neurodegenerative disorders.

中文翻译：

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锌促进tau蛋白的液-液相分离。

Tau是一种微管相关蛋白，在阿尔茨海默氏病（AD）和其他Tauopathies中起主要作用。最近的报道表明，在存在拥挤剂的情况下，tau可以进行液-液相分离（LLPS），形成高度动态的液滴。在这里，使用重组表达的蛋白质，比浊法，荧光显微镜成像和光漂白（FRAP）分析后的荧光回收率，我们表明二价过渡金属锌强烈促进了这一过程，将平衡相边界转移到了较低的蛋白质或拥挤剂浓度。对于任何其他二价过渡金属离子，包括Mn2 +，Fe2 +，Co2 +，Ni2 +，和Cu2 +我们还证明了tau上的多个锌结合位点与LLPS促进作用有关，并提供了对该过程机理的见解。锌的浓度在AD脑中高度升高，并且据信这种金属离子是该疾病发病机理的重要因素。因此，本发现为理解锌稳态与AD和相关神经退行性疾病的致病过程之间的关系提供了新的维度。