Ahmadi Soha, Zhu Shaolong, Sharma Renu, Wu Bing, Soong Ronald, Dutta Majumdar R, Wilson Derek J, Simpson Andre J, Kraatz Heinz-Bernhard
Department of Physical and Environmental Science, University of Toronto Scarborough, 1265 Military Trail, Toronto, Ontario M1C 1A4, Canada.
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 1A1, Canada.
ACS Omega. 2019 Mar 31;4(3):5356-5366. doi: 10.1021/acsomega.8b03595. Epub 2019 Mar 15.
Understanding the factors that give rise to tau aggregation and reactive oxygen species (ROS) is the key aspect in Alzheimer's disease pathogenesis. Microtubule (MT) binding repeats of tau protein were suggested to play a critical role in tau aggregation. Here, we show that the interaction of Cu with full-length MT binding repeats R1-R4 leads to the aggregation, and a Cys-based redox chemistry is critically involved in tau aggregation leading to disulfide-bridge dimerization of R2 and R3 and further aggregation into a fibrillar structure. Notably, ascorbate and glutathione, the most abundant antioxidants in neurons, cannot prevent the effect of Cu on R2 and R3 aggregation. Detailed ESI-MS and NMR experiments demonstrate the interaction of Cu with MT binding repeats. We show that redox activity of copper increases when bound to the MT repeats leading to ROS formation, which significantly contribute to cellular damage and neuron death. Results presented here provide new insights into the molecular mechanism of tau aggregation and ROS formation and suggest a new target domain for tau aggregation inhibitors.
了解导致tau蛋白聚集和活性氧（ROS）产生的因素是阿尔茨海默病发病机制的关键方面。tau蛋白的微管（MT）结合重复序列被认为在tau蛋白聚集中起关键作用。在此，我们表明铜与全长MT结合重复序列R1 - R4的相互作用会导致聚集，并且基于半胱氨酸的氧化还原化学在tau蛋白聚集中起关键作用，导致R2和R3形成二硫键桥二聚体，并进一步聚集成纤维状结构。值得注意的是，神经元中最丰富的抗氧化剂抗坏血酸和谷胱甘肽无法阻止铜对R2和R3聚集的影响。详细的电喷雾电离质谱（ESI - MS）和核磁共振（NMR）实验证明了铜与MT结合重复序列的相互作用。我们表明，铜与MT重复序列结合时氧化还原活性增加，导致ROS形成，这对细胞损伤和神经元死亡有显著影响。此处呈现的结果为tau蛋白聚集和ROS形成的分子机制提供了新见解，并为tau蛋白聚集抑制剂提出了新的靶结构域。
