The etiology of human age-related cataract. Proteins don't last forever.
The etiology of human age-related cataract. Proteins don't last forever.
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DOI：
10.1016/j.bbagen.2015.08.016
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Friedrich MG
中科院分区：
文献类型：
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作者：
Truscott RJ;Friedrich MG
人类白内障的绝大多数可能是由于人类透镜中长寿命大分子的自发分解造成的。长寿蛋白的分解/反应是最重要的，最近的蛋白质组学分析已经能够识别特定的晶体蛋白及其氨基酸修饰的确切位点。对白内障晶状体蛋白质的分析表明，某些结构蛋白质上的某些位点比年龄匹配的正常晶状体显示出更大程度的退化。老化透镜蛋白质最丰富的翻译后修饰是外消旋化。也存在脱酰胺、截短和交联，每一种都是由蛋白质内敏感氨基酸的自发分解引起的。对于理解核性白内障病因学的基础，提出一旦在关键位点发生一定程度的修饰，蛋白质-蛋白质相互作用被破坏，并且透镜浑浊化加剧。由于长寿蛋白质现在被认为存在于身体的许多其他部位，如大脑，因此从老化晶状体降解蛋白质的详细分析中收集的信息将更广泛地应用于其他与年龄相关的人类疾病。
It is probable that the great majority of human cataract results from the spontaneous decomposition of long-lived macromolecules in the human lens. Breakdown/reaction of long-lived proteins is of primary importance and recent proteomic analysis has enabled the identification of the particular crystallins, and their exact sites of amino acid modification. Analysis of proteins from cataractous lenses revealed that there are sites on some structural proteins that show a consistently greater degree of deterioration than age-matched normal lenses. The most abundant posttranslational modification of aged lens proteins is racemization. Deamidation, truncation and crosslinking, each arising from the spontaneous breakdown of susceptible amino acids within proteins, are also present. Fundamental to an understanding of nuclear cataract etiology, it is proposed that once a certain degree of modification at key sites occurs, that protein-protein interactions are disrupted and lens opacification ensues. Since long-lived proteins are now recognized to be present in many other sites of the body, such as the brain, the information gleaned from detailed analyses of degraded proteins from aged lenses will apply more widely to other age-related human diseases.