Phenotypic effects of familial amyotrophic lateral sclerosis mutant Sod alleles in transgenic Drosophila
Phenotypic effects of familial amyotrophic lateral sclerosis mutant Sod alleles in transgenic Drosophila
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DOI：
10.1073/pnas.0136976100
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发表时间：
2003-01-07
影响因子：
11.1
通讯作者：
Sohal, RS
中科院分区：
文献类型：
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作者：
Mockett, RJ;Radyuk, SN;Sohal, RS
一部分家族性肌萎缩性侧索硬化症（familial amyotrophic lateral sclerosis， FAILS）患者表现出编码Cu-Zn超氧化物歧化酶[超氧化物：超氧化物氧化还原酶，EC 1.15.1.1 (SOD)]基因的点突变。在Cu-Zn Sod零背景下，将人类野生型和5个FALS Sod突变基因导入果蝇。与野生型对照相比，Sod缺失果蝇的寿命、谷胱甘肽和蛋氨酸含量、繁殖力、运动能力和对高氧应激的抵抗力显著降低。所有这些表型表现都被一个人类野生型等位基因完全挽救，表达5-10%的野生型SOD活性。将人类突变体和野生型等位基因一起置于果蝇Sod零背景下，也观察到野生型寿命完全恢复。FALS Sod突变单独引起隐性表型，通常涉及低或无法检测到的Sod活性水平，其中：(i)在年轻人中观察到野生型表型的完全恢复，(h)老年人表现出氧化应激突然增加，伴有突然发作的生理损伤，随后是过早死亡。因此，与FALS SOD突变相关的最低SOD活性似乎决定了寿命，而不是通过长期增加氧化应激，而是通过限制维持可行氧化还原环境的时间。然而，在人类患者和转基因FALS小鼠模型中，突变SOD的显性功能获得在果蝇中未被观察到。
A subset of patients suffering from familial amyotrophic lateral sclerosis (FAILS) exhibit point mutations in the gene encoding Cu-Zn superoxide dismutase [superoxide:superoxide oxidoreductase, EC 1.15.1.1 (SOD)]. The human wild-type and five FALS Sod mutant transgenes were introduced into the fruit fly, Drosophila melanogaster, in a Cu-Zn Sod null background. Sod null flies had dramatically decreased life span, glutathione and methionine content, fertility, locomotor activity, and resistance to hyperoxic stress, compared with wild-type controls. All of these phenotypic manifestations were rescued fully by a single human wild-type allele, expressing 5-10% of wild-type SOD activity. Full recovery of wild-type life span was also observed when human mutant and wild-type alleles were placed together in the fly Sod null background. The FALS Sod mutations alone caused a recessive phenotype, usually involving low or undetectable levels of SOD activity, in which: (i) full restoration of the wild-type phenotype was observed among young adults, and (h) older adults exhibited a sudden increase in oxidative stress, accompanied by physiological impairment of abrupt onset, and followed by premature death. Thus, the minimal SOD activity associated with the FALS Sod mutations appears to determine longevity, not by chronically increasing oxidative stress, but by limiting the time in which a viable redox environment can be maintained. However, the dominant gain of function by mutant SOD, which occurs in human patients and in the transgenic mouse model of FALS, is not observed in Drosophila.