Kato Shinsuke, Saeki Yusuke, Aoki Masashi, Nagai Makiko, Ishigaki Aya, Itoyama Yasuto, Kato Masako, Asayama Kohtaro, Awaya Akira, Hirano Asao, Ohama Eisaku
Department of Neuropathology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Nishi-cho 36-1, 683-8504 Yonago, Japan.
Acta Neuropathol. 2004 Feb;107(2):149-58. doi: 10.1007/s00401-003-0791-1. Epub 2003 Nov 27.
Living cells produce reactive oxygen species (ROSs). To protect themselves from these ROSs, the cells have developed both an antioxidant system containing superoxide dismutase 1 (SOD1) and a redox system including peroxiredoxin2 (Prx2, thioredoxin peroxidase) and glutathione peroxidase1 (GPx1): SOD1 converts superoxide radicals into hydrogen peroxide (H2O2), and H2O2 is then converted into harmless water (H2O) and oxygen (O2) by Prx2 and GPx1 that directly regulate the redox system. To clarify the biological significance of the interaction of the redox system (Prx2/GPx1) with SOD1 in SOD1-mutated motor neurons in vivo, we produced an affinity-purified rabbit antibody against Prx2 and investigated the immunohistochemical localization of Prx2 and GPx1 in neuronal Lewy body-like hyaline inclusions (LBHIs) in the spinal cords of familial amyotrophic lateral sclerosis (FALS) patients with a two-base pair deletion at codon 126 and an Ala-->Val substitution at codon 4 in the SOD1 gene, as well as in transgenic rats expressing human SOD1 with H46R and G93A mutations. The LBHIs in motor neurons from the SOD1-mutated FALS patients and transgenic rats showed identical immunoreactivities for Prx2 and GPx1: the reaction product deposits with the antibodies against Prx2 and GPx1 were localized in the LBHIs. In addition, the localizations of the immunoreactivities for SOD1 and Prx2/GPx1 were similar in the inclusions: the co-aggregation of Prx2/GPx1 with SOD1 in neuronal LBHIs in mutant SOD1-related FALS patients and transgenic rats was evident. Based on the fact that Prx2/GPx1 directly regulates the redox system, such co-aggregation of Prx2/GPx1 with SOD1 in neuronal LBHIs may lead to the breakdown of the redox system itself, thereby amplifying the mutant SOD1-mediated toxicity in mutant SOD1-linked FALS patients and transgenic rats expressing human mutant SOD1.
活细胞会产生活性氧（ROS）。为了保护自身免受这些ROS的伤害，细胞已经发展出了一个包含超氧化物歧化酶1（SOD1）的抗氧化系统以及一个包括过氧化物还原酶2（Prx2，硫氧还蛋白过氧化物酶）和谷胱甘肽过氧化物酶1（GPx1）的氧化还原系统：SOD1将超氧自由基转化为过氧化氢（H2O2），然后H2O2被Prx2和GPx1转化为无害的水（H2O）和氧气（O2），Prx2和GPx1直接调节氧化还原系统。为了阐明氧化还原系统（Prx2/GPx1）与SOD1在体内SOD1突变运动神经元中的相互作用的生物学意义，我们制备了一种针对Prx2的亲和纯化兔抗体，并研究了Prx2和GPx1在家族性肌萎缩侧索硬化症（FALS）患者脊髓中神经元路易体样透明包涵体（LBHI）中的免疫组织化学定位，这些患者的SOD1基因第126位密码子有两个碱基对缺失且第4位密码子有丙氨酸到缬氨酸的替换，以及在表达具有H46R和G93A突变的人SOD1的转基因大鼠中。来自SOD1突变的FALS患者和转基因大鼠的运动神经元中的LBHI对Prx2和GPx1显示出相同的免疫反应性：与针对Prx2和GPx1的抗体的反应产物沉积在LBHI中。此外，SOD1和Prx2/GPx1的免疫反应性定位在包涵体中相似：在与突变SOD1相关的FALS患者和转基因大鼠的神经元LBHI中，Prx2/GPx1与SOD1的共聚集是明显的。基于Prx2/GPx1直接调节氧化还原系统这一事实，Prx2/GPx1与SOD1在神经元LBHI中的这种共聚集可能导致氧化还原系统本身的崩溃，从而放大了突变SOD1介导的毒性，在与突变SOD1相关的FALS患者和表达人突变SOD1的转基因大鼠中。
