Qin Biying, Chen Xiaodong, Wang Feng, Wang Yanfeng
Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China.
Tangshan Research Institute, Beijing Institute of Technology, Tangshan, Hebei, China.
Cell Death Discov. 2024 Nov 20;10(1):475. doi: 10.1038/s41420-024-02237-3.
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by the accumulation of amyloid β protein (Aβ) and the hyper-phosphorylation of the microtubule-associated protein Tau. The ubiquitin-proteasome system (UPS) plays a pivotal role in determining the fate of proteins, and its dysregulation can contribute to the buildup of Aβ and Tau. Deubiquitinating enzymes (DUBs), working in conjunction with activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3), actively maintain the delicate balance of protein homeostasis. DUBs specifically remove ubiquitin tags from proteins marked for degradation, thereby averting their proteasomal breakdown. Several DUBs have demonstrated their capacity to regulate the levels of Aβ and Tau by modulating their degree of ubiquitination, underscoring their potential as therapeutic targets for AD. In this context, we present a comprehensive review of AD-associated DUBs and elucidate their physiological roles. Moreover, we delve into the current advancements in developing inhibitors targeting these DUBs, including the determination of cocrystal structures with their respective targets. Additionally, we assess the therapeutic efficacy of these inhibitors in AD, aiming to establish a theoretical foundation for future AD treatments.
阿尔茨海默病（AD）是一种常见的神经退行性疾病，其特征在于淀粉样β蛋白（Aβ）的积累以及微管相关蛋白Tau的过度磷酸化。泛素 - 蛋白酶体系统（UPS）在决定蛋白质的命运中起关键作用，其失调可导致Aβ和Tau的积累。去泛素化酶（DUBs）与激活酶（E1）、泛素结合酶（E2）和泛素连接酶（E3）协同作用，积极维持蛋白质稳态的微妙平衡。DUBs特异性地从标记为降解的蛋白质上移除泛素标签，从而避免其被蛋白酶体分解。几种DUBs已证明能够通过调节Aβ和Tau的泛素化程度来调节它们的水平，凸显了它们作为AD治疗靶点的潜力。在此背景下，我们对与AD相关的DUBs进行了全面综述，并阐明了它们的生理作用。此外，我们深入探讨了开发针对这些DUBs的抑制剂的当前进展，包括与各自靶点的共晶体结构的确定。此外，我们评估了这些抑制剂在AD中的治疗效果，旨在为未来的AD治疗建立理论基础。
