Max Planck Institute of Biochemistry, Department of Cellular Biochemistry, Martinsried, Germany.
Nat Rev Mol Cell Biol. 2019 Jul;20(7):421-435. doi: 10.1038/s41580-019-0101-y.
Ageing is a major risk factor for the development of many diseases, prominently including neurodegenerative disorders such as Alzheimer disease and Parkinson disease. A hallmark of many age-related diseases is the dysfunction in protein homeostasis (proteostasis), leading to the accumulation of protein aggregates. In healthy cells, a complex proteostasis network, comprising molecular chaperones and proteolytic machineries and their regulators, operates to ensure the maintenance of proteostasis. These factors coordinate protein synthesis with polypeptide folding, the conservation of protein conformation and protein degradation. However, sustaining proteome balance is a challenging task in the face of various external and endogenous stresses that accumulate during ageing. These stresses lead to the decline of proteostasis network capacity and proteome integrity. The resulting accumulation of misfolded and aggregated proteins affects, in particular, postmitotic cell types such as neurons, manifesting in disease. Recent analyses of proteome-wide changes that occur during ageing inform strategies to improve proteostasis. The possibilities of pharmacological augmentation of the capacity of proteostasis networks hold great promise for delaying the onset of age-related pathologies associated with proteome deterioration and for extending healthspan.
衰老是许多疾病发展的一个主要风险因素，其中突出的包括神经退行性疾病，如阿尔茨海默病和帕金森病。许多与年龄相关的疾病的一个标志是蛋白质平衡（蛋白质稳态）功能障碍，导致蛋白质聚集物的积累。在健康的细胞中，一个复杂的蛋白质稳态网络，包括分子伴侣和蛋白水解机器及其调节剂，用于确保蛋白质稳态的维持。这些因素协调蛋白质合成与多肽折叠、蛋白质构象的保存和蛋白质降解。然而，面对衰老过程中积累的各种外部和内部应激，维持蛋白质组平衡是一项具有挑战性的任务。这些应激导致蛋白质稳态网络容量和蛋白质组完整性的下降。由此产生的错误折叠和聚集的蛋白质的积累，特别是影响有丝分裂后细胞类型，如神经元，表现为疾病。最近对衰老过程中发生的蛋白质组范围变化的分析为改善蛋白质稳态提供了策略。药理学增强蛋白质稳态网络的能力具有很大的潜力，可以延缓与蛋白质组恶化相关的与年龄相关的病理的发生，并延长健康寿命。
