Enhanced tethered-flight duration and locomotor activity by overexpression of the human gene SOD1 in Drosophila motorneurons

Abstract

Mutation of the human gene superoxide dismutase (hSOD1) is associated with the fatal neurodegenerative disease familial amyotrophic lateral sclerosis (Lou Gehrig’s disease). Selective overexpression of hSOD1 in Drosophila motorneurons increases lifespan to 140% of normal. The current study was designed to determine resistance to lifespan decline and failure of sensorimotor functions by overexpressing hSOD1 in Drosophila‘s motorneurons. First, we measured the ability to maintain continuous flight and wingbeat frequency (WBF) as a function of age (5 to 50 days). Flies overexpressing hSOD1 under the D42-GAL4 activator were able to sustain flight significantly longer than controls, with the largest effect observed in the middle stages of life. The hSOD1-expressed line also had, on average, slower wingbeat frequencies in late, but not early life relative to age-matched controls. Second, we examined locomotor (exploratory walking) behavior in late life when flies had lost the ability to fly (age ≥ 60 d). hSOD1-expressed flies showed significantly more robust walking activity relative to controls. Findings show patterns of functional decline dissimilar to those reported for other life-extended lines, and suggest that the hSOD1 gene not only delays death but enhances sensorimotor abilities critical to survival even in late life.

Aging mechanisms—A perspective mostly from Drosophila

“…Among commonly used assays for assessing healthspan are those that measure movement. These include the negative geotaxis assay for evaluating climbing ability, [31][32][33] and a variety of flight duration, 33,34 and exploratory activity tests. 33,35,36 The movement weakening during aging may be due to skeletal muscle deterioration or cognitive decline and can be further examined using histological T A B L E 1 Suggested assays in Drosophila to investigate traits that contribute to healthspan in humans methods.…”

Tissue-Specific Knockdown of Genes of the Argonaute Family Modulates Lifespan and Radioresistance in Drosophila Melanogaster

“…In our study, knockdown of AGO1 and piwi genes in the nervous system and the fat body caused activation of stress response genes, especially antioxidant defense genes (Sod1, Prx5), genes of DNA damage response and repair (Gadd45, spn-B), and genes encoding heat shock proteins (Hsp27, Hsp68). Several of these genes have been identified previously as pro-longevity genes [33][34][35]42,43]. At the same time, suppression of AGO2 and AGO3 expression mainly reduced the activity of stress response genes.…”

“…In addition, changes in the levels of retrotransposons and expression of stress response genes were analyzed to determine the molecular mechanisms involved. It was previously found that genes of antioxidant defense, DNA damage response, and repair play a critical role in both lifespan regulation and the reaction of cells, tissues, and a whole organism to ionizing irradiation [33][34][35][36][37][38][39][40][41]. In addition, genes involved in different mechanisms of proteostasis demonstrate changes during aging and after irradiation as well [38,39,42,43].…”

Tissue-Specific Knockdown of Genes of the Argonaute Family Modulates Lifespan and Radioresistance in Drosophila melanogaster

“…In our study, knockdown of AGO1 and piwi genes in the nervous system and the fat body caused activation of stress response genes, especially antioxidant defense genes ( Sod1, Prx5 ), genes of DNA damage response and repair ( Gadd45, spn-B ), and genes encoding heat shock proteins ( Hsp27, Hsp68 ). Several of these genes have been identified previously as pro-longevity genes [ 33 , 34 , 35 , 42 , 43 ]. At the same time, suppression of AGO2 and AGO3 expression mainly reduced the activity of stress response genes.…”

“…In addition, changes in the levels of retrotransposons and expression of stress response genes were analyzed to determine the molecular mechanisms involved. It was previously found that genes of antioxidant defense, DNA damage response, and repair play a critical role in both lifespan regulation and the reaction of cells, tissues, and a whole organism to ionizing irradiation [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. In addition, genes involved in different mechanisms of proteostasis demonstrate changes during aging and after irradiation as well [ 38 , 39 , 42 , 43 ].…”