Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly Delhi College of Engineering), Delhi 110042, India.
Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly Delhi College of Engineering), Delhi 110042, India.
Ageing Res Rev. 2020 Aug;61:101078. doi: 10.1016/j.arr.2020.101078. Epub 2020 May 12.
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积累是各种与年龄相关的神经退行性疾病（NDDs）的典型特征，包括阿尔茨海默病、帕金森病、亨廷顿病、肌萎缩侧索硬化症和多发性硬化症。异常蛋白，如阿尔茨海默病中的 Aβ 和 Tau，以及帕金森病中的 α-突触核蛋白，扰乱了大脑中的神经元生理学和细胞内稳态，从而影响了全球数百万人的生命。在这里，泛素蛋白酶体系统（UPS）在清除细胞内有毒代谢物方面起着决定性的作用，据广泛报道，任何异常都会加剧神经退行性病理。尽管在泛素化研究方面取得了很大进展，但针对特定蛋白质泛素化和清除的分子标记物及其机制仍不清楚。因此，本综述证实了 UPS 在大脑信号转导和神经元生理学中的作用，以及其在 NDD 特定致病蛋白清除中的机制作用。此外，还讨论了当前和未来有前途的治疗方法，以针对 UPS 介导的神经退行性变，实现更好的公共健康。
