Expression of human FALS SOD in motorneurons of Drosophila

Mutations in human CuZn superoxide dismutase (SOD) have been associated wit h familial amyotrophic lateral sclerosis (FALS). Although leading to many e xperimental advances, this finding has not yet led to a clear understanding of the biochemical mechanism by which mutations in SOD promote the degener ation of motorneurons that causes this incurable paralytic disease. To expl ore the biochemical mechanism of FALS SOD-mediated neuropathogenesis, we us ed transgenic methodology to target the expression of a human FALS SOD to m otorneurons of Drosophila, an organism known for its: phenotypic sensitivit y to genetic manipulation of SOD. Earlier, we showed that targeted expressi on of human SOD in motorneurons of Drosophila causes a dramatic extension o f adult lifespan (>40%) and rescues most of the phenotypes of SOD-null muta nts. Using the same generic system, we now ash if targeted expression of a mutant allele of human SOD that is associated with FALS causes paralysis an d premature death, or is otherwise injurious in Drosophila as it is in huma ns and transgenic mice. Here we report that high-level expression of a huma n FALS SOD in motorneurons is not detrimental and does not promote paralysi s and premature death when expressed in motorneurons of Drosophila. In shar p contrast, the expression of FALS SOD in Drosophila actually extends lifes pan, 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. (C) 1999 Elsevier Science In c.