Department of Pharmacy, Southeast University, Dhaka, Bangladesh.
Pharmakon Neuroscience Research Network, Dhaka, Bangladesh.
Neurotox Res. 2020 Jun;38(1):8-17. doi: 10.1007/s12640-020-00185-1. Epub 2020 Mar 9.
The ubiquitin (Ub)-proteasome system (UPS) is considered as a central protein degradation system in all eukaryotes. The UPS comprises of several factors such as Ub and Ub-like molecules, Ub hydrolases, E3 Ub ligases, and the proteasome itself. Numerous studies have demonstrated that the dysfunction of UPS plays an essential role in the pathogenesis and progression of Alzheimer's disease (AD). Furthermore, current evidence has suggested that the UPS components can be connected with the initial stage of AD that is characterized by synaptic dysfunction, and to the late phases of AD, marked by neurodegeneration. In AD patients, the accumulations of insoluble protein in the brain can be caused by overload or dysfunction of the UPS, or by conformational alterations in the protein substrates that prevent their degradation and recognition by the UPS. Synaptic dysfunction is also caused by defective proteolysis that has found in the initial stage in AD as the UPS is widely recognized to play a pivotal role in the regular activities of synapses. Conversely, its precise cause and pathogenesis are unclear. Presently accepted medicines for AD give symptomatic relief, though they are unable to stop the progression of the disease. Besides, the components of the cellular quality control system demonstrate a significant emphasis on the advancement of targeted and effective treatments for AD. In this review, we focus on the role of UPS in the pathogenesis of AD and highlight how the UPS-linked treatments influence in the management of AD.
泛素（Ub）-蛋白酶体系统（UPS）被认为是所有真核生物中中央蛋白质降解系统。UPS 由 Ub 和 Ub 样分子、Ub 水解酶、E3 Ub 连接酶和蛋白酶体本身等几个因素组成。大量研究表明，UPS 的功能障碍在阿尔茨海默病（AD）的发病机制和进展中起着至关重要的作用。此外，目前的证据表明，UPS 成分可以与 AD 的早期阶段有关，该阶段以突触功能障碍为特征，并与 AD 的晚期阶段有关，其特征是神经退行性变。在 AD 患者中，大脑中不溶性蛋白质的积累可能是由于 UPS 的过载或功能障碍，或由于蛋白质底物的构象改变，从而阻止它们被 UPS 降解和识别。突触功能障碍也是由缺陷性蛋白水解引起的，在 AD 的早期阶段就已经发现 UPS 广泛被认为在突触的正常活动中起着关键作用。相反，其确切的原因和发病机制尚不清楚。目前用于 AD 的药物只能缓解症状，而不能阻止疾病的进展。此外，细胞质量控制系统的组成部分对 AD 的靶向和有效治疗的进展表现出显著的重视。在这篇综述中，我们重点介绍 UPS 在 AD 发病机制中的作用，并强调 UPS 相关治疗如何影响 AD 的治疗管理。
