Department of Biology & Biochemistry, University of Bath, Bath, UK.
Adv Exp Med Biol. 2020;1233:195-221. doi: 10.1007/978-3-030-38266-7_8.
Alzheimer's disease (AD) is the most common form of dementia, most prevalent in the elderly population and has a significant impact on individuals and their family as well as the health care system and the economy. While the number of patients affected by various forms of dementia including AD is on the increase, there is currently no cure. Although genome-wide association studies have identified genetic markers for familial AD, the molecular mechanisms underlying the initiation and development of both familial and sporadic AD remain poorly understood. Most neurodegenerative diseases and in particular those associated with dementia have been defined as proteinopathies due to the presence of intra- and/or extracellular protein aggregates in the brain of affected individuals. Although loss of proteostasis in AD has been known for decades, it is only in recent years that we have come to appreciate the role of ubiquitin-dependent mechanisms in brain homeostasis and in brain diseases. Ubiquitin is a highly versatile post-translational modification which regulates many aspects of protein fate and function, including protein degradation by the Ubiquitin-Proteasome System (UPS), autophagy-mediated removal of damaged organelles and proteins, lysosomal turnover of membrane proteins and of extracellular molecules brought inside the cell through endocytosis. Amyloid-β (Aβ) fragments as well as hyperphosphorylation of Tau are hallmarks of AD, and these are found in extracellular plaques and intracellular fibrils in the brain of individuals with AD, respectively. Yet, whether it is the oligomeric or the soluble species of Aβ and Tau that mediate toxicity is still unclear. These proteins impact on mitochondrial energy metabolism, inflammation, as well as a number of housekeeping processes including protein degradation through the UPS and autophagy. In this chapter, we will discuss the role of ubiquitin in neuronal homeostasis as well as in AD; summarise crosstalks between the enzymes that regulate protein ubiquitination and the toxic proteins Tau and Aβ; highlight emerging molecular mechanisms in AD as well as future strategies which aim to exploit the ubiquitin system as a source for next-generation therapeutics.
阿尔茨海默病（AD）是最常见的痴呆症形式，在老年人群中最为普遍，对个人及其家庭、医疗保健系统和经济都有重大影响。虽然受各种形式的痴呆症（包括 AD）影响的患者人数正在增加，但目前尚无治愈方法。尽管全基因组关联研究已经确定了家族性 AD 的遗传标记，但家族性和散发性 AD 的发病和发展的分子机制仍知之甚少。大多数神经退行性疾病，特别是与痴呆症相关的疾病，由于受影响个体大脑中存在细胞内和/或细胞外蛋白质聚集体，因此被定义为蛋白质病。尽管 AD 中蛋白质稳态的丧失已经被人们了解了几十年，但直到最近几年，我们才开始认识到泛素依赖性机制在大脑内稳态和大脑疾病中的作用。泛素是一种高度灵活的翻译后修饰，可调节蛋白质命运和功能的许多方面，包括通过泛素-蛋白酶体系统（UPS）进行蛋白质降解、通过自噬清除受损细胞器和蛋白质、溶酶体膜蛋白和通过内吞作用进入细胞的细胞外分子的周转。淀粉样β（Aβ）片段以及 Tau 的过度磷酸化是 AD 的标志，分别存在于 AD 患者大脑中的细胞外斑块和细胞内纤维中。然而，介导毒性的是寡聚体还是可溶性 Aβ 和 Tau 仍然不清楚。这些蛋白质影响线粒体能量代谢、炎症以及许多管家过程，包括通过 UPS 和自噬进行蛋白质降解。在本章中，我们将讨论泛素在神经元内稳态以及 AD 中的作用；总结调节蛋白质泛素化的酶与毒性蛋白 Tau 和 Aβ 之间的串扰；强调 AD 中的新兴分子机制以及旨在利用泛素系统作为下一代治疗药物来源的未来策略。
