title: Wildtype motoneurons, ALS-Linked SOD1 mutation and glutamate profoundly modify astrocyte metabolism and lactate shuttling.
abstract: The selective degeneration of motoneuron that typifies amyotrophic lateral sclerosis (ALS) implicates non-cell-autonomous effects of astrocytes. However, mechanisms underlying astrocyte-mediated neurotoxicity remain largely unknown. According to the determinant role of astrocyte metabolism in supporting neuronal function, we propose to explore the metabolic status of astrocytes exposed to ALS-associated conditions. We found a significant metabolic dysregulation including purine, pyrimidine, lysine, and glycerophospholipid metabolism pathways in astrocytes expressing an ALS-causing mutated superoxide dismutase-1 (SOD1) when co-cultured with motoneurons. SOD1 astrocytes exposed to glutamate revealed a significant modification of the astrocyte metabolic fingerprint. More importantly, we observed that SOD1 mutation and glutamate impact the cellular shuttling of lactate between astrocytes and motoneurons with a decreased in extra- and intra-cellular lactate levels in astrocytes. Based on the emergent strategy of metabolomics, this work provides novel insight for understanding metabolic dysfunction of astrocytes in ALS conditions and opens the perspective of therapeutics targets through focusing on these metabolic pathways. GLIA 2017 GLIA 2017;65:592-605.
authors.affiliation: Université François-Rabelais, INSERM U930 "Imagerie et Cerveau," CHRU de Tours, Tours, France.
authors.forename: Blandine
authors.initials: B
authors.lastname: Madji Hounoum
authors.affiliation: Université François-Rabelais, INSERM U930 "Imagerie et Cerveau," CHRU de Tours, Tours, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mavel
authors.affiliation: The Neuroscience Institute Montpellier, INSERM U1051, Saint Eloi Hospital, Montpellier, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Coque
authors.affiliation: Université François-Rabelais, INSERM U930 "Imagerie et Cerveau," CHRU de Tours, Tours, France.|Laboratoire de Biochimie et de Biologie Moléculaire, Hôpital Bretonneau, CHRU de Tours, Tours, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Patin
authors.affiliation: Université François-Rabelais, INSERM U930 "Imagerie et Cerveau," CHRU de Tours, Tours, France.|Laboratoire de Biochimie et de Biologie Moléculaire, Hôpital Bretonneau, CHRU de Tours, Tours, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Vourc'h
authors.affiliation: Université François-Rabelais, INSERM U930 "Imagerie et Cerveau," CHRU de Tours, Tours, France.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Marouillat
authors.affiliation: Université François-Rabelais, INSERM U930 "Imagerie et Cerveau," CHRU de Tours, Tours, France.|Plateforme Scientifique et Technique "Analyses des Systèmes Biologiques" PST-ASB, Université François-Rabelais, 37032, Tours Cedex 1, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Nadal-Desbarats
authors.affiliation: Université François-Rabelais, INSERM U930 "Imagerie et Cerveau," CHRU de Tours, Tours, France.|Plateforme Scientifique et Technique "Analyses des Systèmes Biologiques" PST-ASB, Université François-Rabelais, 37032, Tours Cedex 1, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Emond
authors.affiliation: Université François-Rabelais, INSERM U930 "Imagerie et Cerveau," CHRU de Tours, Tours, France.|Centre SLA, Service de Neurologie, CHRU de Tours, Tours, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Corcia
authors.affiliation: Université François-Rabelais, INSERM U930 "Imagerie et Cerveau," CHRU de Tours, Tours, France.|Laboratoire de Biochimie et de Biologie Moléculaire, Hôpital Bretonneau, CHRU de Tours, Tours, France.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Andres
authors.affiliation: The Neuroscience Institute Montpellier, INSERM U1051, Saint Eloi Hospital, Montpellier, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Raoul
authors.affiliation: Université François-Rabelais, INSERM U930 "Imagerie et Cerveau," CHRU de Tours, Tours, France.|Laboratoire de Biochimie et de Biologie Moléculaire, Hôpital Bretonneau, CHRU de Tours, Tours, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Blasco
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D053858:Metabolic Networks and Pathways / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism*; D025341:Principal Component Analysis; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D014316:Tritium / Q000378:metabolism
chemical_list: D014316:Tritium; D019344:Lactic Acid; D018698:Glutamic Acid; C470429:SOD1 G37R protein, mouse; D013482:Superoxide Dismutase
keywords: LC-HRMS; NMR; co-culture; cross-talk; excitotoxicity; in vitro model; metabolomics