Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain.: Part II:: dihydropyrimidinase-related protein 2, α-enolase and heat shock cognate 71
Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain.: Part II:: dihydropyrimidinase-related protein 2, α-enolase and heat shock cognate 71
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DOI：
10.1046/j.1471-4159.2002.01103.x
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发表时间：
2002-09-01
影响因子：
4.7
通讯作者：
Butterfield, DA
中科院分区：
文献类型：
--
作者：
Castegna, A;Aksenov, M;Butterfield, DA
阿尔茨海默病（AD）是一种神经退行性疾病，其中氧化应激被认为是病理进展中的重要事件。特别是，它已被证明，活性氧（ROS）的蛋白质修饰发生在AD比在对照脑更大的程度上，这表明在神经退行性变的过程中的蛋白质功能的氧化相关的减少可能的作用。通过测量蛋白质羰基含量评估的对蛋白质的氧化损伤涉及几种事件，例如特定蛋白质功能的丧失、异常蛋白质清除、细胞氧化还原平衡的消耗和细胞周期的干扰，以及最终的神经元死亡。本研究代表了进一步了解蛋白质的氧化修饰和AD中神经元死亡之间的关系。以前，我们使用我们的蛋白质组学方法，成功地替代劳动密集型免疫化学分析，检测蛋白质，并确定肌酸激酶，谷氨酰胺合成酶和泛素羧基末端水解酶L-1在AD脑特异性氧化蛋白。在这份报告中，我们再次应用我们的蛋白质组学方法，以确定新的目标蛋白质氧化在AD下顶叶（IPL）。参与轴突生长和导向的二氢嘧啶酶相关蛋白2（DRP-2）在AD脑中显示蛋白质羰基化水平显著增加，提示其在AD神经网络形成的受损机制中起作用。此外，胞质酶α-烯醇化酶被鉴定为蛋白质氧化的靶点，并参与AD病理事件中的糖酵解途径。最后，热休克同源物71（HSC-71）显示AD脑中的氧化增加，但不显著。这些结果进行了讨论，参考这些氧化修饰的蛋白在AD脑神经退行性变的潜在参与。
Alzheimer's disease (AD) is a neurodegenerative disorder in which oxidative stress has been implicated as an important event in the progression of the pathology. In particular, it has been shown that protein modification by reactive oxygen species (ROS) occurs to a greater extent in AD than in control brain, suggesting a possible role for oxidation-related decrease in protein function in the process of neurodegeneration. Oxidative damage to proteins, assessed by measuring the protein carbonyl content, is involved in several events such as loss in specific protein function, abnormal protein clearance, depletion of the cellular redox-balance and interference with the cell cycle, and, ultimately, neuronal death. The present investigation represents a further step in understanding the relationship between oxidative modification of protein and neuronal death in AD. Previously, we used our proteomics approach, which successfully substitutes for labor-intensive immunochemical analysis, to detect proteins and identified creatine kinase, glutamine synthase and ubiquitin carboxy-terminal hydrolase L-1 as specifically oxidized proteins in AD brain. In this report we again applied our proteomics approach to identify new targets of protein oxidation in AD inferior parietal lobe (IPL). The dihydropyrimidinase related protein 2 (DRP-2), which is involved in the axonal growth and guidance, showed significantly increased level in protein carbonyls in AD brain, suggesting a role for impaired mechanism of neural network formation in AD. Additionally, the cytosolic enzyme alpha-enolase was identified as a target of protein oxidation and is involved the glycolytic pathway in the pathological events of AD. Finally, the heat shock cognate 71 (HSC-71) revealed increased, but not significant, oxidation in AD brain. These results are discussed with reference to potential involvement of these oxidatively modified proteins in neurodegeneration in AD brain.