Upadhyay Arun, Joshi Vibhuti
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Bioscience and Biomedical Engineering, Indian Institute of Technology Bhilai, Chhattisgarh, India.
Subcell Biochem. 2024;107:21-41. doi: 10.1007/978-3-031-66768-8_2.
Ageing is an inevitable phenomenon that remains under control of a plethora of signalling pathways and regulatory mechanisms. Slowing of cellular homeostasis and repair pathways, declining genomic and proteomic integrity, and deficient stress regulatory machinery may cause accumulating damage triggering initiation of pathways leading to ageing-associated changes. Multiple genetic studies in small laboratory organisms focused on the manipulation of proteasomal activities have shown promising results in delaying the age-related decline and improving the lifespan. In addition, a number of studies indicate a prominent role of small molecule-based proteasome activators showing positive results in ameliorating the stress conditions, protecting degenerating neurons, restoring cognitive functions, and extending life span of organisms. In this chapter, we provide a brief overview of the multi-enzyme proteasome complex, its structure, subunit composition and variety of cellular functions. We also highlight the strategies applied in the past to modulate the protein degradation efficiency of proteasome and their impact on rebalancing the proteostasis defects. Finally, we provide a descriptive account of proteasome activation mechanisms and small molecule-based strategies to improve the overall organismal health and delay the development of age-associated pathologies.
衰老 是一种不可避免的现象，仍受众多信号通路和调节机制的控制。细胞稳态和修复通路的减缓、基因组和蛋白质组完整性的下降以及应激调节机制的缺陷，可能会导致累积性损伤，从而触发导致衰老相关变化的通路的启动。在小型实验生物体中进行的多项聚焦于蛋白酶体活性操纵的基因研究，在延缓与年龄相关的衰退和延长寿命方面显示出了有前景的结果。此外，一些研究表明基于小分子的蛋白酶体激活剂具有显著作用，在改善应激条件、保护退化神经元、恢复认知功能以及延长生物体寿命方面显示出积极效果。在本章中，我们简要概述了多酶蛋白酶体复合物、其结构、亚基组成以及多种细胞功能。我们还强调了过去应用于调节蛋白酶体蛋白质降解效率的策略及其对重新平衡蛋白质稳态缺陷的影响。最后，我们对蛋白酶体激活机制以及基于小分子的改善整体机体健康和延缓衰老相关病理发展的策略进行了描述。
