Borchelt D R, Lee M K, Slunt H S, Guarnieri M, Xu Z S, Wong P C, Brown R H, Price D L, Sisodia S S, Cleveland D W
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8292-6. doi: 10.1073/pnas.91.17.8292.
Familial amyotrophic lateral sclerosis (FALS) has been linked to mutations in the homodimeric enzyme Cu/Zn superoxide dismutase 1 (SOD1). Assay by transient expression in primate cells of six FALS mutant enzymes revealed a continuum of enzymatic activity bounded by the enzyme carrying the mutation Gly-85-->Arg, which was inactive, and mutant enzyme G37R carrying the Gly-37-->Arg change, which retained full specific activity but displayed a 2-fold reduction in polypeptide stability. The G37R mutant displayed similar properties in transformed lymphocytes from an individual heterozygous for the G37R and wild-type SOD1 genes; heterodimeric enzymes composed of mutant and wild-type subunits were detected, but there was no measurable diminution in the stability and activity of the wild-type subunits. Thus, for mutants such as G37R, either surprisingly modest losses in activity (involving only the mutant subunit) can yield motor neuron death, or alternatively, mutant SOD1 may acquire properties that injure motor neurons by one or more mechanisms unrelated to the metabolism of oxygen radicals.
家族性肌萎缩侧索硬化症（FALS）与同二聚体酶铜/锌超氧化物歧化酶1（SOD1）的突变有关。通过在灵长类细胞中瞬时表达六种FALS突变酶进行分析，结果显示酶活性呈连续变化，其界限为由携带Gly-85→Arg突变的无活性酶和携带Gly-37→Arg变化的G37R突变酶，后者保留了全部比活性，但多肽稳定性降低了2倍。G37R突变体在来自G37R和野生型SOD1基因杂合个体的转化淋巴细胞中表现出相似的特性；检测到由突变体和野生型亚基组成的异二聚体酶，但野生型亚基的稳定性和活性没有明显降低。因此，对于G37R等突变体，要么令人惊讶地发现适度的活性损失（仅涉及突变体亚基）就能导致运动神经元死亡，要么突变型SOD1可能获得了通过一种或多种与氧自由基代谢无关的机制损伤运动神经元的特性。
