泛素化修饰在阿尔茨海默病发病机制中作用的研究进展

Research advances in the role of ubiquitination in the pathogenesis of Alzheimer's disease

摘要:

阿尔茨海默病（AD）的病理特征主要是β-淀粉样蛋白（Aβ）沉积和神经纤维缠结，均为高度磷酸化与泛素化的tau蛋白组成的蛋白质聚集体。蛋白质泛素化修饰作为调控蛋白质降解的最主要的修饰类型，动态地、多方面地参与了神经细胞凋亡等多个细胞过程。该文综述了泛素化修饰在AD中的作用，包括异常泛素化修饰与AD病理特征之间的关联、泛素–蛋白酶体系统及自噬-溶酶体途径的功能异常对AD的影响，以及去泛素化酶的调控作用。研究发现，tau蛋白和Aβ的异常泛素化与AD的神经退行性变过程密切相关。泛素-蛋白酶体系统的功能障碍导致受损蛋白质在细胞内积聚，形成AD的标志性病理结构。同时，神经炎症中tau蛋白的异常泛素化也起到了关键作用。此外，去泛素化酶作为调节泛素化修饰的关键酶，其活性的抑制有助于促进病理蛋白的降解，为AD治疗提供了新的策略。该文还讨论了去泛素化酶的小分子抑制剂在AD治疗中的潜力，并指出了多靶点、多机制综合性治疗策略的必要性。未来研究应进一步探索泛素化修饰在AD中的具体分子机制，以期发现新的治疗靶点和生物标志物，推动AD治疗策略的发展。

Abstract:

The main pathological features of Alzheimer's disease （AD） include β-amyloid （Aβ） deposition and neurofibrillary tangles， both of which are protein aggregates made up of highly phosphorylated and ubiquitinated tau protein. As the most important type of modification that regulates protein degradation， ubiquitination plays a dynamic and multifaceted role in various cellular processes， including cell apoptosis. This article reviews the role of ubiquitination in AD， including the association between abnormal ubiquitination and the pathological features of AD， the impact of dysfunctions within the ubiquitin-proteasome system （UPS） and autophagy-lysosome pathway on AD， and the regulatory role of deubiquitinating enzymes. Studies have shown that abnormal ubiquitination of tau protein and Aβ is closely associated with the process of neurodegeneration in AD. Dysfunction in the UPS leads to the accumulation of damaged proteins within cells， contributing to the hallmark pathological structures of AD. At the same time， abnormal ubiquitination of tau protein also plays a pivotal role in neuroinflammation. In addition， deubiquitinating enzymes are key enzymes for regulating ubiquitination， and inhibition of their activity may enhance the degradation of pathological proteins， which provides new strategies for the treatment of AD. This article discusses the potential of small-molecule inhibitors targeting deubiquitinating enzymes in the treatment of AD and points out the necessity of comprehensive treatment strategies involving multiple targets and mechanisms. Future studies should delve deeper into the specific molecular mechanisms of ubiquitination in AD， in order to identify new treatment targets and biomarkers and promote the development of treatment strategies for AD.