期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：1
页码：301-306
DOI：10.1073/pnas.0136976100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：A subset of patients suffering from familial amyotrophic lateral sclerosis (FALS) 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 (ii) 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.
