Aging and regulated protein degradation: who has the UPPer hand?
Aging and regulated protein degradation: who has the UPPer hand?
复制标题
DOI：
10.1111/j.1474-9726.2007.00329.x
复制
发表时间：
2007-10
期刊：
影响因子：
7.8
通讯作者：
Vita A. Vernace-;T. Schmidt-Glenewinkel;M. Figueiredo-Pereira
中科院分区：
文献类型：
--
作者：
Vita A. Vernace-;T. Schmidt-Glenewinkel;M. Figueiredo-Pereira
在所有细胞中，蛋白质降解是一个持续不断的过程，对细胞存活和修复至关重要。泛素/蛋白酶体途径（UPP）是以调节方式降解细胞内蛋白的主要蛋白水解途径。它在许多细胞过程和疾病中起着关键作用。UPP的破坏与引起异常蛋白质积累的病理生理学状况特别相关，例如在衰老以及包括阿尔茨海默病和帕金森病在内的各种神经退行性疾病中。由于未知的原因，大多数这些神经退行性疾病，包括家族性和散发性病例表现出迟发性。这些神经退行性疾病可能表现出迟发性，因为蛋白酶体活性随着年龄的增长而降低。由蛋白酶体介导的蛋白水解的衰老依赖性损伤可能对细胞活力具有深远的影响。它可导致细胞中修饰的潜在毒性蛋白质的积累，并可通过凋亡或坏死引起细胞损伤或过早细胞死亡。虽然人们普遍认为衰老会影响UPP的功能，但问题是为什么衰老会导致UPP调节的蛋白质降解下降？在此，我们回顾了UPP的一些特性和介导其年龄依赖性损伤的机制。我们还讨论了这些发现的相关性，提出UPP功能障碍可能是衰老的里程碑之一。
In all cells, protein degradation is a constant, ongoing process that is critical for cell survival and repair. The ubiquitin/proteasome pathway (UPP) is the major proteolytic pathway that degrades intracellular proteins in a regulated manner. It plays critical roles in many cellular processes and diseases. Disruption of the UPP is particularly relevant to pathophysiological conditions that provoke the accumulation of aberrant proteins, such as in aging as well as in a variety of neurodegenerative disorders including Alzheimer's and Parkinson's diseases. For unknown reasons, most of these neurodegenerative disorders that include familial and sporadic cases exhibit a late onset. It is possible that these neurodegenerative conditions exhibit a late onset because proteasome activity decreases with aging. Aging‐dependent impairment in proteolysis mediated by the proteasome may have profound ramifications for cell viability. It can lead to the accumulation of modified, potentially toxic proteins in cells and can cause cell injury or premature cell death by apoptosis or necrosis. While it is accepted that aging affects UPP function, the question is why does aging cause a decline in regulated protein degradation by the UPP? Herein, we review some of the properties of the UPP and mechanisms mediating its age‐dependent impairment. We also discuss the relevance of these findings leading to a model that proposes that UPP dysfunction may be one of the milestones of aging.