SUPEROXIDE-DISMUTASE-1 WITH MUTATIONS LINKED TO FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS POSSESSES SIGNIFICANT ACTIVITY
SUPEROXIDE-DISMUTASE-1 WITH MUTATIONS LINKED TO FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS POSSESSES SIGNIFICANT ACTIVITY
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DOI：
10.1073/pnas.91.17.8292
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发表时间：
1994-08-16
影响因子：
11.1
通讯作者：
CLEVELAND, DW
中科院分区：
文献类型：
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作者：
BORCHELT, DR;LEE, MK;CLEVELAND, DW
家族性肌萎缩侧索硬化症（FALS）与同二聚体酶Cu/Zn超氧化物歧化酶1（SOD 1）的突变有关。通过在灵长类细胞中瞬时表达六种FALS突变酶的测定揭示了由携带突变Gly-85 --> Arg的酶和携带Gly-37 --> Arg变化的突变酶G37 R限制的酶活性的连续性，所述突变酶G37 R是无活性的，其保留了完全的比活性，但显示多肽稳定性降低2倍。G37 R突变体显示出类似的性质，从一个人的G37 R和野生型SOD 1基因杂合转化淋巴细胞的异二聚体酶组成的突变体和野生型亚基进行检测，但没有可测量的减少野生型亚基的稳定性和活性。因此，对于突变体如G37 R，或者令人惊讶的适度活性损失（仅涉及突变亚基）可导致运动神经元死亡，或者突变SOD 1可获得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性质。
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.