Modulating Longevity in Drosophila by Over- and Underexpression of Glutamate-Cysteine Ligase

摘要

A notable extension of life span (up to 50%) was achievedin Drosophila melanogaster when the catalytic subunit of glutamate-cysteine ligase (GCLc) was overexpressed in neuronal tissue, while amoderate increase (up to 24%) was observed when the modulatory sub-unit of GCL (GCLm) was overexpressed globally. We sought to iden-tify specific tissue domains that are particularly sensitive to the benefi-cial effects of GCLc overexpression. Overexpression of GCLc using themushroom body driver (0K107-GAL4) had a small but significant ben-eficial effect on longevity (approximately 12%) while overexpression inserotonergic (MZ360-GAL4) neurons or dopaminergic and serotonergicneurons (Ddc-GAL4) had small, nonsignificant effects on longevity. Asignificant beneficial effect (12-13%) was also observed using the C23-GAL4 transverse muscle driver. Finally, a low-level global driver (ar-madillo) was shown to increase life span significantly (15%). A seriesof mutant and knockdown studies were also carried out. Reduction ofGCLm by > 95% had no discernable effect on longevity or resistanceto oxidative stress. In contrast, knockdown of GCLc by 30-70% usingan RNAi-hairpin strategy had a significant effect, resulting in greatersensitivity to H_2O_2and reduced survivorship under normal conditionsvarying from a 50% reduction in median life span to lethality. A GCLcnull allele was identified and shown to be recessive lethal. Overall, thisstudy demonstrates that the longevity effects of GCLc are dependent ondosage and that there are specific tissues (mushroom bodies, motor neu-rons, and transverse muscle cells) particularly sensitive to the benefits ofGCLc overexpression.