Shibata N, Hirano A, Yamamoto T, Kato Y, Kobayashi M
Department of Pathology, Tokyo Women's Medical University, Japan.
Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Jun;1(3):143-61. doi: 10.1080/14660820050515151.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron system involvement, and is epidemiologically subclassified into sporadic, familial and endemic forms. About 20% of ALS families are associated with mutations in the gene for superoxide dismutase-1 (SOD1) encoded on chromosome 21q22.1. Several studies have pointed to a variety of functions of mutant SOD1, which has enhanced catalytic activity of the peroxynitrite-mediated tyrosine nitration, readily releases the reactive Cu ions, induces apoptotic cell death, has enhanced peroxidase activity, damages the mitochondria to release Ca2+, and forms SOD1-containing aggregates in the cytoplasm. Many of these studies have obtained evidence for increased oxidative damage in ALS. On the other hand, some reports disagree with oxidative damage involvement in SOD1 mutant ALS. In considering the findings of increased oxidative damage in mutant SOD1-expressing transgenic mice, it should be remembered that overexpression of mutant SOD1 may enhance oxidative stress generation from this enzyme. In this review, we present the clinicopathological features of SOD1 mutant familial ALS and its transgenic mouse model, and also discuss SOD1 mutation-related neurotoxicity, including SOD1 protein aggregation and post-translational protein modification.
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，其特征为运动神经元系统受累，在流行病学上可分为散发性、家族性和地方性三种类型。约20%的ALS家族与位于21号染色体21q22.1上的超氧化物歧化酶1（SOD1）基因突变有关。多项研究指出了突变型SOD1的多种功能，包括增强过氧亚硝酸盐介导的酪氨酸硝化的催化活性、易于释放活性铜离子、诱导细胞凋亡、增强过氧化物酶活性、损害线粒体以释放Ca2+以及在细胞质中形成含SOD1的聚集体。许多这些研究都获得了ALS中氧化损伤增加的证据。另一方面，一些报告不同意氧化损伤与SOD1突变型ALS有关。在考虑在表达突变型SOD1的转基因小鼠中氧化损伤增加的研究结果时，应该记住，突变型SOD1的过表达可能会增强该酶产生的氧化应激。在这篇综述中，我们介绍了SOD1突变型家族性ALS及其转基因小鼠模型的临床病理特征，并讨论了与SOD1突变相关的神经毒性，包括SOD1蛋白聚集和翻译后蛋白修饰。
