Department of Biological Sciences, Hunter College of City University of New York, 695 Park Avenue, New York, NY 10065, USA.
Apoptosis. 2010 Nov;15(11):1292-311. doi: 10.1007/s10495-010-0466-z.
The ubiquitin/proteasome pathway is the major proteolytic quality control system in cells. In this review we discuss the impact of a deregulation of this pathway on neuronal function and its causal relationship to the intracellular deposition of ubiquitin protein conjugates in pathological inclusion bodies in all the major chronic neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases as well as amyotrophic lateral sclerosis. We describe the intricate nature of the ubiquitin/proteasome pathway and discuss the paradox of protein aggregation, i.e. its potential toxic/protective effect in neurodegeneration. The relations between some of the dysfunctional components of the pathway and neurodegeneration are presented. We highlight possible ubiquitin/proteasome pathway-targeting therapeutic approaches, such as activating the proteasome, enhancing ubiquitination and promoting SUMOylation that might be important to slow/treat the progression of neurodegeneration. Finally, a model time line is presented for neurodegeneration starting at the initial injurious events up to protein aggregation and cell death, with potential time points for therapeutic intervention.
泛素/蛋白酶体途径是细胞中主要的蛋白质降解质量控制系统。在这篇综述中，我们讨论了该途径的失调对神经元功能的影响，以及它与所有主要慢性神经退行性疾病（如阿尔茨海默病、帕金森病和亨廷顿病以及肌萎缩侧索硬化症）中细胞内泛素蛋白缀合物沉积的因果关系。我们描述了泛素/蛋白酶体途径的复杂性质，并讨论了蛋白质聚集的悖论，即其在神经退行性变中的潜在毒性/保护作用。还介绍了该途径的一些功能失调成分与神经退行性变之间的关系。我们强调了一些可能的泛素/蛋白酶体途径靶向治疗方法，例如激活蛋白酶体、增强泛素化和促进 SUMO 化，这些方法可能对减缓/治疗神经退行性变的进展很重要。最后，提出了一个从初始损伤事件到蛋白质聚集和细胞死亡的神经退行性变时间线模型，并提出了潜在的治疗干预时间点。
