Proteomic analysis of 4-hydroxy-2-nonenal-modified proteins in G93A-SOD1 transgenic mice - A model of familial amyotrophic lateral sclerosis
Proteomic analysis of 4-hydroxy-2-nonenal-modified proteins in G93A-SOD1 transgenic mice - A model of familial amyotrophic lateral sclerosis
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DOI：
10.1016/j.freeradbiomed.2004.12.021
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发表时间：
2005-04-01
影响因子：
7.4
通讯作者：
Butterfield, DA
中科院分区：
文献类型：
--
作者：
Perluigi, M;Poon, HF;Butterfield, DA
肌萎缩侧索硬化症（ALS）是一种年龄相关的致命性运动神经元退行性疾病，偶尔发生（sALS）和遗传性（fALS），遗传病例约占诊断的10%。虽然多种机制可能有助于ALS运动神经元损伤的发病机制，但最近的进展表明，氧化应激可能在疾病的扩大和可能的起始中发挥重要作用。脂质过氧化是氧化应激的几种结果之一。由于中枢神经系统（CNS）富含多不饱和脂肪酸，因此特别容易受到膜相关氧化应激的影响。细胞膜脂质或循环脂蛋白分子的过氧化产生高活性醛，其中包括4-羟基-2-壬烯醛（HNE）。ALS患者脊髓运动神经元HNE水平升高，提示ALS运动神经元变性与脂质过氧化有关。在本研究中，我们使用了一种平行的蛋白质组学方法来确定HNE修饰的蛋白质在脊髓组织的模型ALS，G93 A-SOD 1转基因小鼠，相比于非转基因小鼠。我们在G93 A-SOD 1转基因小鼠的脊髓中发现了三种显著的HNE修饰的蛋白：二氢嘧啶酶相关蛋白2（DRP-2），热休克蛋白70（Hsp 70），以及可能的a.烯醇化酶这些结果支持氧化应激作为ALS发病机制中的主要机制的作用。结构的改变和功能蛋白的活性下降可能始终有助于ALS的神经退行性变过程。(c)2004年爱思唯尔公司All rights reserved.
Amyotrophic lateral sclerosis (ALS) is an age-related, fatal motor neuron degenerative disease occurring both sporadically (sALS) and heritably (fALS), with inherited cases accounting for approximately 10% of diagnoses. Although multiple mechanisms likely contribute to the pathogenesis of motor neuron injury in ALS, recent advances suggest that oxidative stress may play a significant role in the amplification, and possibly the initiation, of the disease. Lipid peroxidation is one of the several outcomes of oxidative stress. Since the central nervous system (CNS) is enriched with polyunsaturated fatty acids, it is particularly vulnerable to membrane-associated oxidative stress. Peroxidation of cellular membrane lipids or circulating lipoprotein molecules generates highly reactive aldehydes, among which is 4-hydroxy-2-nonenal (HNE). HNE levels are increased in spinal cord motor neurons of ALS patients, indicating that lipid peroxidation is associated with the motor neuron degeneration in ALS. In the present study, we used a parallel proteomic approach to identify HNE-modified proteins in the spinal cord tissue of a model of fALS, G93A-SOD1 transgenic mice, in comparison to the nontransgenic mice. We found three significantly HNE-modified proteins in the spinal cord of G93A-SOD1 transgenic mice: dihydropyrimidinase-related protein 2 (DRP-2), heat-shock protein 70 (Hsp70), and possibly a.-enolase. These results support the role of oxidative stress as a major mechanism in the pathogenesis of ALS. Structural alteration and activity decline of functional proteins may consistently contribute to the neurodegeneration process in ALS. (c) 2004 Elsevier Inc. All rights reserved.