Therapy through chaperones: Sense or antisense? - Cystic fibrosis as a model disease
Therapy through chaperones: Sense or antisense? - Cystic fibrosis as a model disease
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DOI：
10.1007/s10545-006-0251-x
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发表时间：
2006-04-01
影响因子：
4.2
通讯作者：
Amaral, MD
中科院分区：
文献类型：
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作者：
Amaral, MD
单个异常蛋白质的大量产生和积累可能会对细胞构成主要的毒性负担，甚至危及生物体的长期生存能力。因此，适应和生存迫使进化建立“细胞质量控制”机制，检测、监测并经常降解这种异常折叠的基因产物，其中分子伴侣是关键角色。尽管如此，仍然有许多错误折叠的蛋白质的例子，尽管这些蛋白质被细胞质量控制识别为异常并被有效地丢弃，但仍然保留了它们的野生型对应蛋白的一些功能特性，因此它们在细胞中的维持将对有机体有利。本文介绍了分子伴侣在细胞中的作用，以及对分子伴侣影响人类疾病发展机制的一些新见解，这些疾病是由导致蛋白质错误折叠的突变引起的。特别强调囊性纤维化，这是一种经典的遗传性疾病，由内质网质量控制导致突变的、尽管具有功能的蛋白质的保留和降解所致。这个特殊的系统是一个很好的例子来描述一些蛋白质底物可能共享的机制，定义突变体的共同特征，以及识别它们保留和降解的机制干预因素。最后，讨论了纠正蛋白质折叠缺陷的新方法，包括分子伴侣(例如，通过RNA干扰)作为新的治疗靶点的潜力，以及化学或药物伴侣作为新的治疗试剂的使用。
Massive production and accumulation of a single abnormal protein may constitute a major toxic burden for the cell and even compromise the organism's long-term viability. Consequently, adaptation and survival have forced evolution to create 'Cyquality control' mechanisms that detect, monitor, and often degrade such abnormally folded gene products, in which molecular chaperones are key players. Notwithstanding this, there are numerous examples of misfolded proteins which, in spite of being recognized as aberrant and efficiently discarded by cellular quality control, still retain some of the functional properties of their wild-type counterparts, so that their maintenance in the cell would be beneficial for the organism. Herein are described the cellular roles of molecular chaperones and some new insights on the mechanisms by which they influence the development of human diseases caused by mutations that lead to protein misfolding. A special emphasis is given to cystic fibrosis, a classical genetic disorder resulting from the retention and degradation of a mutant, albeit functional, protein by the endoplasmic reticulum quality control. This particular system has been a good example to describe the mechanisms that are likely to be shared by a number of protein substrates, to define the common characteristics of the mutants, as well as to identify the mechanistic intervenients in their retention and degradation. Finally, new approaches aimed at correcting protein folding defects are discussed, including the potential of molecular chaperones (e.g., through RNA interference) as novel therapeutic targets, and the usage of chemical or pharmacological chaperones as new therapeutic agents.