Department of Neurological Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Mol Psychiatry. 2022 Jan;27(1):259-268. doi: 10.1038/s41380-021-01233-8. Epub 2021 Jul 20.
Neurodegenerative diseases (NDs) are characterized by the aggregation of neurotoxic proteins in the central nervous system. Aberrant protein accumulation in NDs is largely caused by the dysfunction of the two principal protein catabolism pathways, the ubiquitin-proteasome system (UPS), and the autophagy-lysosomal pathway (ALP). The two protein quality control pathways are bridged by ubiquitination, a post-translational modification that can induce protein degradation via both the UPS and the ALP. Perturbed ubiquitination leads to the formation of toxic aggregates and inclusion bodies that are deleterious to neurons. Ubiquitination is promoted by a cascade of ubiquitinating enzymes and counter-regulated by deubiquitinating enzymes (DUBs). As fine-tuning regulators of ubiquitination and protein degradation, DUBs modulate the stability of ND-associated pathogenic proteins including amyloid β protein, Tau, and α-synuclein. Besides, DUBs also influence ND-associated mitophagy, protein secretion, and neuroinflammation. Given the various and critical functions of DUBs in NDs, DUBs may become potential therapeutic targets for NDs.
神经退行性疾病（NDs）的特征是中枢神经系统中神经毒性蛋白的聚集。NDs 中异常蛋白的积累在很大程度上是由于两种主要的蛋白质降解途径——泛素蛋白酶体系统（UPS）和自噬溶酶体途径（ALP）的功能障碍所致。这两种蛋白质质量控制途径通过泛素化连接在一起，泛素化是一种翻译后修饰，可以通过 UPS 和 ALP 诱导蛋白质降解。泛素化的紊乱导致有毒聚集体和包含体的形成，对神经元有害。泛素化由一系列泛素化酶促进，并受到去泛素化酶（DUBs）的反向调节。作为泛素化和蛋白质降解的精细调节因子，DUBs 调节包括淀粉样β蛋白、Tau 和 α-突触核蛋白在内的与 ND 相关的致病蛋白的稳定性。此外，DUBs 还影响与 ND 相关的线粒体自噬、蛋白质分泌和神经炎症。鉴于 DUBs 在 NDs 中的各种关键功能，DUBs 可能成为 NDs 的潜在治疗靶点。
