Studies on genes that control lifespan through genome-wide misexpression screen & spastic paraplegia gene atl in Drosophila

Abstract

Recent studies suggest that genetic modulation is important in determining animal life-span. To identify genes controlling life-span, we examined 29,790 Drosophila EP lines expressing Gal4, which induces overexpression or antisense-RNA of the gene adjacent to an EP element. Our analyses identified 9 genes associated with increased life-span. Many of the genes support previous hypotheses on aging while others suggest new mechanisms. Further characterization of these novel genes will reveal the underlying genetic mechanisms of ageing conserved across the phyla. Hereditary spastic paraplegias (HSPs) are human genetic disorders causing increased stiffness and overactive muscle reflexes in the lower extremities. atlastin (atl) is one of the major genes in which mutations result in HSP. We generated a Drosophila model of HSP that has a null mutation in atl. As they aged, atl null flies were paralyzed by mechanical shock such as bumping or vortexing. Furthermore, the flies showed age-dependent degeneration of dopaminergic neurons. These phenotypes were rescued by targeted expression of atl in dopaminergic neurons or feeding L-DOPA or SK&F 38393, an agonist of dopamine receptor. Our data raised the possibility that one of the causes of HSP disease symptoms in human patients with alt mutations is malfunction or degeneration of dopaminergic neurons.