The abnormal accumulation of neurotoxic proteins is the typical hallmark of various age-related neurodegenerative disorders (NDDs), including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis and Multiple sclerosis. The anomalous proteins, such as Aβ, Tau in Alzheimer’s disease and α-synuclein in Parkinson’s disease, perturb the neuronal physiology and cellular homeostasis in the brain thereby affecting the millions of human lives across the globe. Here, ubiquitin proteasome system (UPS) plays a decisive role in clearing the toxic metabolites in cells, where any aberrancy is widely reported to exaggerate the neurodegenerative pathologies. In spite of well-advancement in the ubiquitination research, their molecular markers and mechanisms for target-specific protein ubiquitination and clearance remained elusive. Therefore, this review substantiates the role of UPS in the brain signaling and neuronal physiology with their mechanistic role in the NDD’s specific pathogenic protein clearance. Moreover, current and future promising therapies are discussed to target UPS-mediated neurodegeneration for better public health.

神经毒性蛋白的异常蓄积是各种与年龄有关的神经退行性疾病（NDD）的典型标志，包括阿尔茨海默氏病，帕金森氏病，亨廷顿氏病，肌萎缩性侧索硬化症和多发性硬化症。异常蛋白，例如Aβ，阿尔茨海默氏病中的Tau和帕金森氏病中的α-突触核蛋白，扰乱了大脑的神经元生理和细胞稳态，从而影响了全球数以百万计的人类生命。在这里，泛素蛋白酶体系统（UPS）在清除细胞中的有毒代谢产物中起决定性作用，据报道，任何异常均会夸大神经退行性病变。尽管泛素化研究进展顺利，它们的分子标记和靶标特异性蛋白泛素化和清除的机制仍然难以捉摸。因此，本综述通过其在NDD特异性致病蛋白清除中的作用机制，证实了UPS在脑信号传导和神经元生理中的作用。此外，讨论了当前和未来有希望的疗法，以靶向UPS介导的神经退行性变，以改善公共卫生。