title: Altered Metabolic Profiles Associate with Toxicity in SOD1G93AAstrocyte-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 expressed only in astrocytes and not in neurons. To examine metabolic changes in astrocyte-spinal neuron co-cultures, we carried out metabolomic analysis by1H NMR spectroscopy of media from astrocyte-spinal neuron co-cultures and astrocyte-only cultures. We observed increased glucose uptake with SOD1G93Aexpression in all co-cultures, but while co-cultures with only SOD1G93Aneurons had lower extracellular lactate, those with only SOD1G93Aastrocytes exhibited the reverse. Reduced branched-chain amino acid uptake and increased accumulation of 3-methyl-2-oxovalerate were observed in co-culture with only SOD1G93Aneurons 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 SOD1G93Acell 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.
authors.affiliation: Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK.
authors.forename: Gabriel N
authors.identifier: 0000-0001-6825-7214
authors.initials: GN
authors.lastname: Valbuena
authors.affiliation: Department of Neuroscience, IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", 20156, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Tortarolo
authors.affiliation: Department of Neuroscience, IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", 20156, Milan, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", 20156, Milan, Italy. lavinia.cantoni@guest.marionegri.it.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Cantoni
authors.affiliation: Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK. h.keun@imperial.ac.uk.
authors.forename: Hector C
authors.initials: HC
authors.lastname: Keun
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D055442:Metabolome; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism*; D018384:Oxidative Stress; D000072105:Superoxide Dismutase-1 / Q000378:metabolism*
chemical_list: D018698:Glutamic Acid; D000072105:Superoxide Dismutase-1; D005947:Glucose