Phenotypic Effects of Familial Amyotrophic Lateral Sclerosis Mutant Sod Alleles in Transgenic Drosophila

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-01, Vol.100 (1), p.301-306
• Main Authors: Mockett, Robin J., Radyuk, Svetlana N., Benes, Judith J., Orr, William C., Sohal, Rajindar S.
• Format: Article
• Language: English
• Subjects: Aging; Alleles; Amino Acid Substitution; Amyotrophic lateral sclerosis; Animals; Animals, Genetically Modified; Biological Sciences; DNA Primers; Drosophila; Drosophila melanogaster - genetics; Drosophila melanogaster - growth & development; Drosophila melanogaster - physiology; Genes; Genetic mutation; Glutathione - metabolism; Humans; Insects; Life Expectancy; Life span; Male animals; Methionine - metabolism; Motor Neuron Disease - enzymology; Motor Neuron Disease - genetics; Mutagenesis, Site-Directed; Mutation; Neurology; Oxidative stress; Phenotype; Polymerase Chain Reaction; Superoxide Dismutase - genetics; Time Factors; Transgenes; Transgenic plants
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0136976100

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.