Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.
College of Medical Sciences, Yobe State University, Damaturu P.M.B. 1144, Nigeria.
Cells. 2021 Mar 22;10(3):703. doi: 10.3390/cells10030703.
The self-assembly of tau into paired helical filaments (PHFs) in neurofibrillary tangles (NFTs) is a significant event in Alzheimer's disease (AD) pathogenesis. Numerous post-translational modifications enhance or inhibit tau assembly into NFTs. Oxidative stress, which accompanies AD, induces multiple post-translational modifications in proteins, including the formation of dityrosine (DiY) cross-links. Previous studies have revealed that metal-catalysed oxidation (MCO) using Cu and HO leads to the formation of DiY cross-links in two misfolding proteins, Aβ and α-synuclein, associated with AD and Parkinson's disease respectively. The effect of MCO on tau remains unknown. Here, we examined the effect of MCO and ultra-violet oxidation to study the influence of DiY cross-linking on the self-assembly of the PHF-core tau fragment. We report that DiY cross-linking facilitates tau assembly into tau oligomers that fail to bind thioflavin S, lack β-sheet structure and prevents their elongation into filaments. At a higher concentration, Cu (without HO) also facilitates the formation of these tau oligomers. The DiY cross-linked tau oligomers do not cause cell death. Our findings suggest that DiY cross-linking of pre-assembled tau promotes the formation of soluble tau oligomers that show no acute impact on cell viability.
tau 自组装成双螺旋纤维（PHF）在神经纤维缠结（NFTs）中是阿尔茨海默病（AD）发病机制中的一个重要事件。许多翻译后修饰增强或抑制 tau 组装成 NFTs。氧化应激伴随着 AD，导致蛋白质发生多种翻译后修饰，包括二酪氨酸（DiY）交联的形成。先前的研究表明，Cu 和 HO 介导的金属催化氧化（MCO）导致与 AD 和帕金森病相关的两种错误折叠蛋白 Aβ和α-突触核蛋白中 DiY 交联的形成。MCO 对 tau 的影响尚不清楚。在这里，我们检查了 MCO 和超氧化的作用，以研究 DiY 交联对 PHF 核心 tau 片段自组装的影响。我们报告说，DiY 交联促进 tau 组装成 tau 寡聚物，这些寡聚物不能结合硫黄素 S，缺乏β-折叠结构，并阻止它们延伸成纤维。在更高的浓度下，Cu（没有 HO）也促进这些 tau 寡聚物的形成。DiY 交联的 tau 寡聚物不会导致细胞死亡。我们的发现表明，预组装的 tau 的 DiY 交联促进了可溶性 tau 寡聚物的形成，这些寡聚物对细胞活力没有急性影响。
