title: Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron death. ALS can be induced by mutations in the superoxide dismutase 1 gene (SOD1). Evidence for the non-cell-autonomous nature of ALS emerged from the observation that wild-type glial cells extended the survival of SOD1 mutant motor neurons in chimeric mice. To uncover the contribution of astrocytes to human motor neuron degeneration, we cocultured hESC-derived motor neurons with human primary astrocytes expressing mutated SOD1. We detected a selective motor neuron toxicity that was correlated with increased inflammatory response in SOD1-mutated astrocytes. Furthermore, we present evidence that astrocytes can activate NOX2 to produce superoxide and that effect can be reversed by antioxidants. We show that NOX2 inhibitor, apocynin, can prevent the loss of motor neurons caused by SOD1-mutated astrocytes. These results provide an assay for drug screening using a human ALS in vitro astrocyte-based cell model.
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Maria C N
authors.initials: MC
authors.lastname: Marchetto
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
authors.forename: Yangling
authors.initials: Y
authors.lastname: Mu
authors.forename: Alan M
authors.initials: AM
authors.lastname: Smith
authors.forename: Gabriela G
authors.initials: GG
authors.lastname: Cezar
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
mesh_terms: D000098:Acetophenones / Q000494:pharmacology / Q000627:therapeutic use; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D001681:Biological Assay / Q000379:methods; D002450:Cell Communication / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism / Q000633:toxicity
chemical_list: D000098:Acetophenones; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; C000606290:SOD1 protein, human; D013481:Superoxides; C056165:acetovanillone; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases