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ALS-linked SOD1 in glial cells enhances ß-N-Methylamino L-Alanine (BMAA)-induced toxicity in Drosophila.

ABSTRACT: Environmental factors have been implicated in the etiology of a number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the role of environmental agents in ALS remains poorly understood. To this end, we used transgenic fruit flies (Drosophila melanogaster) to explore the interaction between mutant superoxide dismutase 1 (SOD1) and chemicals such as ß-N-methylamino L-alanine (BMAA), the herbicide agent paraquat, and superoxide species. We expressed ALS-linked human SOD1 (hSOD1A4V, and hSOD1G85R), hSOD1wt as well as the Drosophila native SOD1 (dSOD1) in motoneurons (MNs) or in glial cells alone and simultaneously in both types of cells. We then examined the effect of BMAA (3 mM), paraquat (20 mM), and hydrogen peroxide (H2O2, 1%) on the lifespan of SOD1-expressing flies. Our data show that glial expression of mutant and wild type hSOD1s reduces the ability of flies to climb. Further, we show that while all three chemicals significantly shorten the lifespan of flies, mutant SOD1 does not have a significant additional effect on the lifespan of flies fed on paraquat, but further shortens the lifespan of flies fed on H2O2. Finally, we show that BMAA shows a dramatic cell-type specific effect with mutant SOD1. Flies with expression of mutant hSOD1 in MNs survived longer on BMAA compared to control flies. In contrast, BMAA significantly shortened the lifespan of flies expressing mutant hSOD1 in glia. Consistent with a neuronal protection role, flies expressing these mutant hSOD1s in both MNs and glia also lived longer. Hence, our studies reveal a synergistic effect of mutant SOD1 with H2O2 and novel roles for mutant hSOD1s in neurons to reduce BMAA toxicity and in glia to enhance the toxicity of BMAA in flies.

SUBMITTER: Islam R

PROVIDER: S-EPMC3945777 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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ALS-linked SOD1 in glial cells enhances ß-N-Methylamino L-Alanine (BMAA)-induced toxicity in Drosophila.

Islam Rafique R Kumimoto Emily L EL Bao Hong H Zhang Bing B

F1000Research 20121109

Environmental factors have been implicated in the etiology of a number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the role of environmental agents in ALS remains poorly understood. To this end, we used transgenic fruit flies (Drosophila melanogaster) to explore the interaction between mutant superoxide dismutase 1 (SOD1) and chemicals such as ß-N-methylamino L-alanine (BMAA), the herbicide agent paraquat, and superoxide species. We expressed ALS-linked ...[more]

PMID: 24627764

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Project description:Amyotrophic Lateral Sclerosis (ALS) is generally a late onset neurodegenerative disease. Mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene accounts for approximately 20% of familial ALS and 2% of all ALS cases. Although a number of hypothesis have been proposed to explain mutant SOD1 toxicity, the molecular mechanisms of the disease remain unclear. SOD1 linked ALS is thought to function in a non-cell autonomous manner such that the motoneurons are critical for the onset and glia contribute to the progress of the disease. To dissect the roles of motoneurons and glia, we used the Gal4-UAS system to determine gene expression changes following the expression of mutant human SOD1 (G85R) selectively in either motoneurons or glia, and concurrently in motoneurons and glia of flies. We conducted a microarray on young (5 days old) and old (45 days old) flies expressing G85R in these cell types and identified a number of genes involved in a variety of processes. The candidate genes identified by this screen may help elucidate the individual and combined contributions of motoneurons and glial cells in ALS. We used microarrays to evaluate the transcriptional profile of 5 day old and 45 day old flies expressing mutant human SOD1 (G85R) in a tissue specific manner in motoneurons, glia, and together in motoneurons and glia and compared the expression to flies expressing wild-type drosophila SOD1 controls. The Gal4-UAS system was used to drive tissue expression of either mutant human SOD1 (G85R) or wild-type drosophila SOD1 (dSOD1) in flies. Flies containing either the motoneuronal driver, D42-Gal4, the glial driver, M1B-Gal4, or the combined motoneuronal and glial drivers, D42+M1B-Gal4 were crossed to flies containing either mutant human SOD1, UAS-G85R, or wild-type drosophila SOD1, UAS-dSOD1, as a control. Adult male progeny were collected within 24 hours after eclosion and aged to 5 (5d) and 45 (45d) days old. Groups of 10 flies were maintained in vials of cornmeal agar food and transferred to fresh food every 5-7 days. For each Gal4-UAS line and each age, 3 biological replicates consisting of 40 whole flies were flash frozen in liquid nitrogen and used to isolate total RNA, for a total of 36 samples.

Dataset Information

ALS-linked SOD1 in glial cells enhances ß-N-Methylamino L-Alanine (BMAA)-induced toxicity in Drosophila.

Publications

ALS-linked SOD1 in glial cells enhances ß-N-Methylamino L-Alanine (BMAA)-induced toxicity in Drosophila.

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