Tsuda T, Munthasser S, Fraser P E, Percy M E, Rainero I, Vaula G, Pinessi L, Bergamini L, Vignocchi G, McLachlan D R
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Neuron. 1994 Sep;13(3):727-36. doi: 10.1016/0896-6273(94)90039-6.
Mutations in the Cu, Zn superoxide dismutase (SOD1) gene have been reported in some pedigrees with Familial Amyotrophic Lateral Sclerosis (FALS). We have investigated the functional and structural effects of a Gly-->Ser mutation at codon 41 of SOD1 in a pedigree with FALS and the topography of SOD1 expression in the mammalian CNS. These analyses show that the 41Gly-->Ser mutation causes a 27% reduction in Cu, Zn SOD activity. SOD1 is transcribed at high levels in rat motoneurons and four other types of neurons homologous to upper motoneurons that degenerate in human ALS. However, SOD1 is transcribed at lower levels in other types of neurons, such as cerebellar Purkinje cells, which are not usually involved significantly in human ALS. On the other hand, immunocytochemical studies indicate that most types of rat neurons contain similar levels of Cu, Zn SOD immunoreactive protein. Nevertheless, these results suggest that the essential feature causing this subtype of ALS is either a reduction in Cu, Zn SOD activity in cell types that presumably critically require Cu, Zn SOD for protection against oxidative damage or the fact that the mutation in SOD1 associated with FALS results in a novel gain of function that is particularly deleterious to those cell types expressing SOD1 at high levels.
在一些家族性肌萎缩侧索硬化症（FALS）家系中，已报道铜锌超氧化物歧化酶（SOD1）基因发生突变。我们研究了一个FALS家系中SOD1第41位密码子由甘氨酸突变为丝氨酸所产生的功能和结构效应，以及SOD1在哺乳动物中枢神经系统中的表达定位。这些分析表明，41Gly→Ser突变导致铜锌超氧化物歧化酶活性降低27%。SOD1在大鼠运动神经元以及与人类肌萎缩侧索硬化症中退化的上运动神经元同源的其他四种神经元类型中高水平转录。然而，SOD1在其他类型的神经元中，如小脑浦肯野细胞，转录水平较低，这些细胞通常在人类肌萎缩侧索硬化症中不显著受累。另一方面，免疫细胞化学研究表明，大多数类型的大鼠神经元含有相似水平的铜锌超氧化物歧化酶免疫反应蛋白。尽管如此，这些结果表明，导致这种肌萎缩侧索硬化症亚型的基本特征要么是在可能严重需要铜锌超氧化物歧化酶来抵御氧化损伤的细胞类型中铜锌超氧化物歧化酶活性降低，要么是与FALS相关的SOD1突变导致了一种新的功能获得，这种功能对那些高水平表达SOD1的细胞类型特别有害。
