Altered Metabolic Profiles Associate with Toxicity in SOD1G93A Astrocyte-Neuron Co-Cultures
Abstract Non-cell autonomous processes involving astrocytes have been shown to contribute to motor neuron degeneration in amyotrophic lateral sclerosis. Mutant superoxide dismutase 1 (SOD1G93A) expression in astrocytes is selectively toxic to motor neurons in co-culture, even when mutant protein is...
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2017-03-01
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doaj-ba9554b5484c44d4be33b5d7672298cf2020-12-08T02:28:09ZengNature Publishing GroupScientific Reports2045-23222017-03-017111410.1038/s41598-017-00072-4Altered Metabolic Profiles Associate with Toxicity in SOD1G93A Astrocyte-Neuron Co-CulturesGabriel N. Valbuena0Massimo Tortarolo1Caterina Bendotti2Lavinia Cantoni3Hector C. Keun4Department of Surgery and Cancer, Faculty of Medicine, Imperial College LondonDepartment of Neuroscience, IRCCS- Istituto di Ricerche Farmacologiche “Mario Negri”Department of Neuroscience, IRCCS- Istituto di Ricerche Farmacologiche “Mario Negri”Department of Molecular Biochemistry and Pharmacology, IRCCS- Istituto di Ricerche Farmacologiche “Mario Negri”Department of Surgery and Cancer, Faculty of Medicine, Imperial College LondonAbstract Non-cell autonomous processes involving astrocytes have been shown to contribute to motor neuron degeneration in amyotrophic lateral sclerosis. Mutant superoxide dismutase 1 (SOD1G93A) expression in astrocytes is selectively toxic to motor neurons in co-culture, even when mutant protein is expressed only in astrocytes and not in neurons. To examine metabolic changes in astrocyte-spinal neuron co-cultures, we carried out metabolomic analysis by 1H NMR spectroscopy of media from astrocyte-spinal neuron co-cultures and astrocyte-only cultures. We observed increased glucose uptake with SOD1G93A expression in all co-cultures, but while co-cultures with only SOD1G93A neurons had lower extracellular lactate, those with only SOD1G93A astrocytes exhibited the reverse. Reduced branched-chain amino acid uptake and increased accumulation of 3-methyl-2-oxovalerate were observed in co-culture with only SOD1G93A neurons while glutamate was reduced in all co-cultures expressing SOD1G93A. The shifts in these coupled processes suggest a potential block in glutamate processing that may impact motor neuron survival. We also observed metabolic alterations which may relate to oxidative stress responses. Overall, the different metabolite changes observed with the two SOD1G93A cell types highlight the role of the astrocyte-motor neuron interaction in the resulting metabolic phenotype, requiring further examination of altered met abolic pathways and their impact on motor neuron survival.https://doi.org/10.1038/s41598-017-00072-4 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gabriel N. Valbuena Massimo Tortarolo Caterina Bendotti Lavinia Cantoni Hector C. Keun |
spellingShingle |
Gabriel N. Valbuena Massimo Tortarolo Caterina Bendotti Lavinia Cantoni Hector C. Keun Altered Metabolic Profiles Associate with Toxicity in SOD1G93A Astrocyte-Neuron Co-Cultures Scientific Reports |
author_facet |
Gabriel N. Valbuena Massimo Tortarolo Caterina Bendotti Lavinia Cantoni Hector C. Keun |
author_sort |
Gabriel N. Valbuena |
title |
Altered Metabolic Profiles Associate with Toxicity in SOD1G93A Astrocyte-Neuron Co-Cultures |
title_short |
Altered Metabolic Profiles Associate with Toxicity in SOD1G93A Astrocyte-Neuron Co-Cultures |
title_full |
Altered Metabolic Profiles Associate with Toxicity in SOD1G93A Astrocyte-Neuron Co-Cultures |
title_fullStr |
Altered Metabolic Profiles Associate with Toxicity in SOD1G93A Astrocyte-Neuron Co-Cultures |
title_full_unstemmed |
Altered Metabolic Profiles Associate with Toxicity in SOD1G93A Astrocyte-Neuron Co-Cultures |
title_sort |
altered metabolic profiles associate with toxicity in sod1g93a astrocyte-neuron co-cultures |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-03-01 |
description |
Abstract Non-cell autonomous processes involving astrocytes have been shown to contribute to motor neuron degeneration in amyotrophic lateral sclerosis. Mutant superoxide dismutase 1 (SOD1G93A) expression in astrocytes is selectively toxic to motor neurons in co-culture, even when mutant protein is expressed only in astrocytes and not in neurons. To examine metabolic changes in astrocyte-spinal neuron co-cultures, we carried out metabolomic analysis by 1H NMR spectroscopy of media from astrocyte-spinal neuron co-cultures and astrocyte-only cultures. We observed increased glucose uptake with SOD1G93A expression in all co-cultures, but while co-cultures with only SOD1G93A neurons had lower extracellular lactate, those with only SOD1G93A astrocytes exhibited the reverse. Reduced branched-chain amino acid uptake and increased accumulation of 3-methyl-2-oxovalerate were observed in co-culture with only SOD1G93A neurons while glutamate was reduced in all co-cultures expressing SOD1G93A. The shifts in these coupled processes suggest a potential block in glutamate processing that may impact motor neuron survival. We also observed metabolic alterations which may relate to oxidative stress responses. Overall, the different metabolite changes observed with the two SOD1G93A cell types highlight the role of the astrocyte-motor neuron interaction in the resulting metabolic phenotype, requiring further examination of altered met abolic pathways and their impact on motor neuron survival. |
url |
https://doi.org/10.1038/s41598-017-00072-4 |
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