The endoplasmic reticulum stress response in aging and age-related diseases.
The endoplasmic reticulum stress response in aging and age-related diseases.
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DOI：
10.3389/fphys.2012.00263
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发表时间：
2012
影响因子：
4
通讯作者：
Naidoo N
中科院分区：
文献类型：
--
作者：
Brown MK;Naidoo N
内质网（ER）是一个多功能细胞器，蛋白质折叠，脂质生物合成和钙储存在其中发生。能量或营养物质的消耗、钙或氧化还原状态的干扰等干扰破坏内质网稳态，导致蛋白质错误折叠、内质网应激和几种被称为未折叠蛋白反应（UPR）的信号通路上调。UPR的特点是诱导伴侣蛋白，降解错误折叠的蛋白质和衰减蛋白质翻译。UPR在维持细胞稳态中起着基本作用，因此是正常生理的中心。然而，持续未解决的内质网应激导致细胞凋亡。衰老相关的关键内质网分子伴侣和折叠酶的表达和活性下降损害了适当的蛋白质折叠和UPR的适应性反应。解释与年龄相关的细胞功能下降和与年龄相关的疾病的一种机制是伴随系统的逐渐失效。在许多这类疾病中，蛋白质或蛋白质片段从其通常可溶的形式转化为不可溶的原纤维或斑块，积聚在包括肝、脑或脾在内的各种器官中。这类疾病通常发生在晚年，包括阿尔茨海默氏症、帕金森氏症、II型糖尿病，以及一系列不太为人所知但往往同样严重的疾病，如致命性家族性失眠症。UPR与许多这些神经退行性和家族性蛋白质折叠疾病以及几种癌症和一系列炎症性疾病（包括糖尿病、动脉粥样硬化、炎症性肠病和关节炎）有关。本文将讨论内质网应激反应的年龄相关变化以及UPR在年龄相关疾病中的作用。
The endoplasmic reticulum(ER) is a multifunctional organelle within which protein folding, lipid biosynthesis, and calcium storage occurs. Perturbations such as energy or nutrient depletion, disturbances in calcium or redox status that disrupt ER homeostasis lead to the misfolding of proteins, ER stress and up-regulation of several signaling pathways coordinately called the unfolded protein response (UPR). The UPR is characterized by the induction of chaperones, degradation of misfolded proteins and attenuation of protein translation. The UPR plays a fundamental role in the maintenance of cellular homeostasis and thus is central to normal physiology. However, sustained unresolved ER stress leads to apoptosis. Aging linked declines in expression and activity of key ER molecular chaperones and folding enzymes compromise proper protein folding and the adaptive response of the UPR. One mechanism to explain age associated declines in cellular functions and age-related diseases is a progressive failure of chaperoning systems. In many of these diseases, proteins or fragments of proteins convert from their normally soluble forms to insoluble fibrils or plaques that accumulate in a variety of organs including the liver, brain or spleen. This group of diseases, which typically occur late in life includes Alzheimer's, Parkinson's, type II diabetes and a host of less well known but often equally serious conditions such as fatal familial insomnia. The UPR is implicated in many of these neurodegenerative and familial protein folding diseases as well as several cancers and a host of inflammatory diseases including diabetes, atherosclerosis, inflammatory bowel disease and arthritis. This review will discuss age-related changes in the ER stress response and the role of the UPR in age-related diseases.
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