Specific binding of Hsp27 and phosphorylated Tau mitigates abnormal Tau aggregation-induced pathology.
Specific binding of Hsp27 and phosphorylated Tau mitigates abnormal Tau aggregation-induced pathology.
复制标题
Hsp27 和磷酸化 Tau 的特异性结合可减轻 Tau 聚集引起的异常病理
DOI：
10.7554/elife.79898
复制
发表时间：
2022-09-01
期刊：
影响因子：
7.7
通讯作者：
Li, Dan
中科院分区：
文献类型：
--
作者：
Zhang, Shengnan;Zhu, Yi;Lu, Jinxia;Liu, Zhenying;Lobato, Amanda G.;Zeng, Wen;Liu, Jiaqi;Qiang, Jiali;Zeng, Shuyi;Zhang, Yaoyang;Liu, Cong;Liu, Jun;He, Zhuohao;Zhai, R. Grace;Li, Dan
磷酸化 Tau (pTau) 的淀粉样蛋白聚集成神经原纤维缠结与阿尔茨海默病 (AD) 密切相关。据报道，几种分子伴侣可以结合 Tau 并阻止其病理性聚集。最近发现 AD 患者大脑中 Hsp27 水平升高，表明其在 pTau 病理学中发挥重要作用。然而，Hsp27 在 pTau 聚集中的分子机制仍知之甚少。在这里，我们发现 Hsp27 与 AD 患者大脑中的 pTau 缠结部分共定位。值得注意的是，微管亲和力调节激酶 2 (MARK2) 对 Tau 的磷酸化可显着增强 Hsp27 与 Tau 的结合亲和力。此外，Hsp27 可在体外有效防止 pTau 纤维颤动，并减轻果蝇 tau 病模型中 pTau 聚集的神经病理学。进一步的机制研究表明，Hsp27 利用其 N 端结构域直接与 pTau 的多个磷酸化位点相互作用进行特异性结合。我们的工作为Hsp27对致病性pTau的特异性识别提供了结构基础，并强调了Hsp27在预防AD中pTau异常聚集和病理学中的重要作用。
Amyloid aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles is closely associated with Alzheimer’s disease (AD). Several molecular chaperones have been reported to bind Tau and impede its pathological aggregation. Recent findings of elevated levels of Hsp27 in the brains of patients with AD suggested its important role in pTau pathology. However, the molecular mechanism of Hsp27 in pTau aggregation remains poorly understood. Here, we show that Hsp27 partially co-localizes with pTau tangles in the brains of patients with AD. Notably, phosphorylation of Tau by microtubule affinity regulating kinase 2 (MARK2), dramatically enhances the binding affinity of Hsp27 to Tau. Moreover, Hsp27 efficiently prevents pTau fibrillation in vitro and mitigates neuropathology of pTau aggregation in a Drosophila tauopathy model. Further mechanistic study reveals that Hsp27 employs its N-terminal domain to directly interact with multiple phosphorylation sites of pTau for specific binding. Our work provides the structural basis for the specific recognition of Hsp27 to pathogenic pTau, and highlights the important role of Hsp27 in preventing abnormal aggregation and pathology of pTau in AD.
影响因子：
--
作者：
Schwarz L;Vollmer G;Richter-Landsberg C
通讯作者：
Richter-Landsberg C