Nakano R
Department of Neurology, Niigata University.
Rinsho Shinkeigaku. 1995 Dec;35(12):1546-8.
Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder affecting primarily upper and lower motor neurons. In all cases of ALS, approximately 5-10% of cases are familial (FALS). Missense mutations in the Cu/Zn superoxide dismutase (SOD1) gene on chromosome 21 have been demonstrated in some families of FALS since 1993. We have also identified a novel missense mutation (substitution of Thr for Ala4) in exon 1 in a Japanese FALS family, and clarified the pathological findings of a patient in this family were typical of FALS with posterior column involvement. However, the mechanism by which the mutations in SOD1 lead to ALS is unknown. It is now clear that the mutations in SOD1 reduce total SOD activities only by 30-60%, and there is doubt whether a reduction in enzymatic function of this magnitude suffices to cause the neuronal loss. Recently, transgenic mice expressing the mutant SOD1 demonstrate motor neuron degeneration despite an increased level of SOD activity. The process of motor neuron degeneration in FALS might be mediated by some novel functions of the mutant SOD1 protein.
肌萎缩侧索硬化症是一种致命的神经退行性疾病，主要影响上下运动神经元。在所有肌萎缩侧索硬化症病例中，约5%-10%为家族性病例（家族性肌萎缩侧索硬化症，FALS）。自1993年以来，在一些家族性肌萎缩侧索硬化症家族中已证实21号染色体上的铜/锌超氧化物歧化酶（SOD1）基因存在错义突变。我们还在一个日本家族性肌萎缩侧索硬化症家族的外显子1中鉴定出一种新的错义突变（Ala4被Thr取代），并明确该家族一名患者的病理表现为典型的伴有后柱受累的家族性肌萎缩侧索硬化症。然而，SOD1突变导致肌萎缩侧索硬化症的机制尚不清楚。现在已经明确，SOD1突变仅使总SOD活性降低30%-60%，并且这种程度的酶功能降低是否足以导致神经元丢失仍存在疑问。最近，表达突变型SOD1的转基因小鼠尽管SOD活性水平升高，但仍表现出运动神经元变性。家族性肌萎缩侧索硬化症中运动神经元变性的过程可能由突变型SOD1蛋白的一些新功能介导。
