Redox system expression in the motor neurons in amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS, superoxide dismutase 1 (SOD1)-mutated familial ALS, and SOD1-mutated ALS animal models
Redox system expression in the motor neurons in amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS, superoxide dismutase 1 (SOD1)-mutated familial ALS, and SOD1-mutated ALS animal models
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DOI：
10.1007/s00401-005-1019-3
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发表时间：
2005-08-01
影响因子：
12.7
通讯作者：
Ohama, E
中科院分区：
文献类型：
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作者：
Kato, S;Kato, M;Ohama, E
过氧化还原蛋白-LL (Prxll) 和谷胱甘肽过氧化物酶-1 (GPxl) 是氧化还原系统的调节剂，氧化还原系统是神经元中最重要的支持系统之一。该系统是一种抗氧化酶防御系统，并与其他重要的细胞支持系统同步连接。为了阐明受肌萎缩侧索硬化症（ALS）影响的残余运动神经元的共同自我生存机制，我们检查了来自两个不同家族（移码126突变和A4 V）的40名散发性ALS（SALS）患者和5名超氧化物歧化酶1（SOD1）突变家族性ALS（FALS）患者以及四种不同菌株的SOD1突变ALS模型的运动神经元（H46R/G93A 大鼠和 G1H/G1L-G93A 小鼠）。我们从氧化还原系统的角度研究了运动神经元中 Prxll/GPxl 的免疫组织化学表达。在正常受试者中，人、大鼠和小鼠的正常脊髓前角中的PrxII/GPxl免疫反应性主要在神经元中被鉴定：在几乎所有运动神经元中观察到细胞质染色。从组织学角度来看，ALS 中脊髓运动神经元的数量随着疾病进展而减少。免疫组织化学显示，Prxll/GPxl 阴性的神经元数量随着 ALS 疾病的进展而增加。然而，在 SALS 患者、SOD1 突变的 FALS 患者和 ALS 动物模型的一些病例的整个临床过程中观察到一些残留的共表达 Prxll/GPxl 的运动神经元。特别是，过度表达 Prxll/GPxl 的运动神经元，即显示氧化还原系统上调的神经元，在 ALS 的临床过程中通常很明显。对于SALS患者，过度表达Prxll/GPx1的运动神经元主要出现在发病后约3年内，并且随着疾病的进展，这些过度表达的神经元数量急剧减少。对于 SOD1 突变的 FALS 患者，与 SALS 患者一样，某些不包含包涵体的残余运动神经元在短期存活的 FALS 患者中也过度表达 Prxll/GPxl。在 ALS 动物模型中，与人类疾病一样，某些残留的运动神经元在其临床过程中表现出 Prxll/GPxl 的过度表达。然而，在 ALS 的末期，观察到神经元中这种常见的 Prxll/GPx1 过度表达机制的破坏。这些发现使我们得出这样的结论：显示氧化还原系统上调的残余 ALS 神经元不太容易受到 ALS 应激的影响，并保护自己免受 ALS 神经元死亡的影响，而这种氧化还原系统在疾病晚期阶段的崩溃会加速神经元变性和/或神经元死亡的过程。
Peroxiredoxin-LL (Prxll) and glutathione peroxidase-l (GPxl) are regulators of the redox system that is one of the most crucial supporting systems in neurons. This system is an antioxidant enzyme defense system and is synchronously linked to other important cell supporting systems. To clarify the common self-survival mechanism of the residual motor neurons affected by amyotrophic lateral sclerosis (ALS), we examined motor neurons from 40 patients with sporadic ALS (SALS) and 5 patients with superoxide dismutase 1 (SOD1)-mutated familial ALS (FALS) from two different families (frame-shift 126 mutation and A4 V) as well as four different strains of the SOD1-mutated ALS models (H46R/G93A rats and G1H/G1L-G93A mice). We investigated the immunohistochemical expression of Prxll/GPxl in motor neurons from the viewpoint of the redox system. In normal subjects, Prxll/GPxl immunoreactivity in the anterior horns of the normal spinal cords of humans, rats and mice was primarily identified in the neurons: cytoplasmic staining was observed in almost all of the motor neurons. Histologically, the number of spinal motor neurons in ALS decreased with disease progression. Immunohistochemically, the number of neurons negative for Prxll/GPxl increased with ALS disease progression. Some residual motor neurons coexpressing Prxll/GPxl were, however, observed throughout the clinical courses in some cases of SALS patients, SOD1-mutated FALS patients, and ALS animal models. In particular, motor neurons overexpressing Prxll/GPxl, i.e., neurons showing redox system up-regulation, were commonly evident during the clinical courses in ALS. For patients with SALS, motor neurons overexpressing Prxll/GPx1 were present mainly within approximately 3 years after disease onset, and these overexpressing neurons thereafter decreased in number dramatically as the disease progressed. For SOD1-mutated FALS patients, like in SALS patients, certain residual motor neurons without inclusions also overexpressed Prxll/GPxl in the short-term-surviving FALS patients. In the ALS animal models, as in the human diseases, certain residual motor neurons showed overexpression of Prxll/GPxl during their clinical courses. At the terminal stage of ALS, however, a disruption of this common Prxll/GPx1-overexpression mechanism in neurons was observed. These findings lead us to the conclusion that the residual ALS neurons showing redox system up-regulation would be less susceptible to ALS stress and protect themselves from ALS neuronal death, whereas the breakdown of this redox system at the advanced disease stage accelerates neuronal degeneration and/or the process of neuronal death.