title: Expression of human FALS SOD in motorneurons of Drosophila.
abstract: Mutations in human CuZn superoxide dismutase (SOD) have been associated with familial amyotrophic lateral sclerosis (FALS). Although leading to many experimental advances, this finding has not yet led to a clear understanding of the biochemical mechanism by which mutations in SOD promote the degeneration of motorneurons that causes this incurable paralytic disease. To explore the biochemical mechanism of FALS SOD-mediated neuropathogenesis, we used transgenic methodology to target the expression of a human FALS SOD to motorneurons of Drosophila, an organism known for its phenotypic sensitivity to genetic manipulation of SOD. Earlier, we showed that targeted expression of human SOD in motorneurons of Drosophila causes a dramatic extension of adult lifespan (>40%) and rescues most of the phenotypes of SOD-null mutants. Using the same genetic system, we now ask if targeted expression of a mutant allele of human SOD that is associated with FALS causes paralysis and premature death, or is otherwise injurious in Drosophila as it is in humans and transgenic mice. Here we report that high-level expression of a human FALS SOD in motorneurons is not detrimental and does not promote paralysis and premature death when expressed in motorneurons of Drosophila. In sharp contrast, the expression of FALS SOD in Drosophila actually extends lifespan, augments resistance to oxidative stress and partially rescues SOD-null mutants in a manner predicted by our earlier studies on the expression of wildtype human SOD in Drosophila motorneurons.
authors.affiliation: Program in Developmental Biology, Hospital for Sick Children, Toronto, Canada.
authors.forename: A J
authors.initials: AJ
authors.lastname: Elia
authors.forename: T L
authors.initials: TL
authors.lastname: Parkes
authors.forename: K
authors.initials: K
authors.lastname: Kirby
authors.forename: P
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: G L
authors.initials: GL
authors.lastname: Boulianne
authors.forename: J P
authors.initials: JP
authors.lastname: Phillips
authors.forename: A J
authors.initials: AJ
authors.lastname: Hilliker
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D004330:Drosophila / Q000201:enzymology* / Q000235:genetics* / Q000254:growth & development; D015870:Gene Expression; D018390:Gene Targeting; D006801:Humans; D008136:Longevity / Q000235:genetics / Q000502:physiology; D051379:Mice; D009046:Motor Neurons / Q000201:enzymology*; D009154:Mutation; D018384:Oxidative Stress; D010641:Phenotype; D013482:Superoxide Dismutase / Q000235:genetics*
chemical_list: D013482:Superoxide Dismutase