Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States.
Elife. 2022 Sep 1;11:e79898. doi: 10.7554/eLife.79898.
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 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.
磷酸化 Tau（pTau）的淀粉样聚集与阿尔茨海默病（AD）密切相关。已有报道称，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 病理中的重要作用。然而，HSP27 在 pTau 聚集中的分子机制仍知之甚少。本研究显示，Hsp27 部分与 AD 患者大脑中的 pTau 缠结共定位。值得注意的是，微管亲和调节激酶 2（MARK2）对 Tau 的磷酸化，显著增强了 Hsp27 与 Tau 的结合亲和力。此外，Hsp27 可有效防止 Tau 在体外纤维形成，并减轻 Tau 聚集病变模型中的神经病理学损伤。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，实现特异性结合。本研究为 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 异常聚集和病理损伤中的重要作用。
