Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Biochem Pharmacol. 2018 Dec;158:207-216. doi: 10.1016/j.bcp.2018.10.030. Epub 2018 Oct 28.
Ageing is defined as a time-dependent functional decline that occurs in most of live organisms. Brain modification during the ageing process has been considered to predispose to neurodegenerative disorders. Despite intensive research, the exact mechanisms accounting for the switch from physiological brain ageing to neurodegeneration remain to be fully elucidated. At a cellular level, brain ageing is characterized by growing inflammation, oxidative stress, increased genomic instability, altered metabolism and the destruction of protein homeostasis, which causes the accumulation of cellular waste. In this respect, the ubiquitin proteasome system and autophagy represent the two main proteolytic systems accountable for misfolded proteins degradation in neurons. Not surprisingly, the impairment of these systems has been reported in ageing and neurodegenerative disorders characterized by inclusions of protein aggregates. Herein, we provide an overview of the molecular mechanisms that regulate ageing and neurodegenerative disorders, in particular those linked to an alteration of protein degradation. Moreover, the current therapeutic and nutritional interventions used to target protein degradation pathways are explored and discussed in the prospective of stalling or even reversing ageing and neurodegenerative processes.
衰老是指大多数生物体内发生的与时间相关的功能衰退。人们认为大脑在衰老过程中的改变易导致神经退行性疾病。尽管进行了深入的研究，但仍未完全阐明导致生理脑衰老向神经退行性变转变的确切机制。在细胞水平上，大脑衰老的特征是炎症、氧化应激、基因组不稳定性增加、代谢改变和蛋白质动态平衡破坏，从而导致细胞废物的积累。在这方面，泛素蛋白酶体系统和自噬代表了两种主要的蛋白水解系统，负责降解神经元中错误折叠的蛋白质。毫不奇怪，在以蛋白质聚集体包涵物为特征的衰老和神经退行性疾病中，已经报道了这些系统的损伤。在此，我们概述了调节衰老和神经退行性疾病的分子机制，特别是与蛋白质降解改变相关的机制。此外，还探讨和讨论了目前用于靶向蛋白质降解途径的治疗和营养干预措施，以期延缓甚至逆转衰老和神经退行性过程。
