研究人员通过系统分析人类三方基序（TRIM）蛋白，发现了一些能有效抑制tau聚集的TRIM。其中，TRIM11在阿尔茨海默病（AD）大脑中明显下调。TRIM11能促进突变tau和多余的正常tau的蛋白酶体降解。它还通过作为分子伴侣防止tau错误折叠和作为分解酶溶解预先形成的tau纤维来提高tau的可溶性。TRIM11能保持神经元的连接性和活力。
通过腺相关病毒颅内输送TRIM11可改善多种tau病理动物模型的病理学、神经炎症和认知障碍。这些结果表明，TRIM11的下调是tau病理的发病机制之一，恢复TRIM11的表达可能是一种有效的治疗策略。
据介绍，tau聚集成丝状内含物是AD和其他多种神经退行性tau病理的基础。tau病理的发病机理尚不清楚，这阻碍了改变疾病的治疗方法的开发。
附：英文原文
Title: TRIM11 protects against tauopathies and is down-regulated in Alzheimer’s disease
Author: Zi-Yang Zhang, Dilshan S. Harischandra, Ruifang Wang, Shivani Ghaisas, Janet Y. Zhao, Thomas P. McMonagle, Guixin Zhu, Kenzo D. Lacuarta, Jianing Song, John Q. Trojanowski, Hong Xu, Virginia M.-Y. Lee, Xiaolu Yang
Issue&Volume: 2023-07-28
Abstract: Aggregation of tau into filamentous inclusions underlies Alzheimer’s disease (AD) and numerous other neurodegenerative tauopathies. The pathogenesis of tauopathies remains unclear, which impedes the development of disease-modifying treatments. Here, by systematically analyzing human tripartite motif (TRIM) proteins, we identified a few TRIMs that could potently inhibit tau aggregation. Among them, TRIM11 was markedly down-regulated in AD brains. TRIM11 promoted the proteasomal degradation of mutant tau as well as superfluous normal tau. It also enhanced tau solubility by acting as both a molecular chaperone to prevent tau misfolding and a disaggregase to dissolve preformed tau fibrils. TRIM11 maintained the connectivity and viability of neurons. Intracranial delivery of TRIM11 through adeno-associated viruses ameliorated pathology, neuroinflammation, and cognitive impairments in multiple animal models of tauopathies. These results suggest that TRIM11 down-regulation contributes to the pathogenesis of tauopathies and that restoring TRIM11 expression may represent an effective therapeutic strategy.
DOI: add6696
Source: https://www.science.org/doi/full/10.1126/science.add6696