title: Pathogenic effects of amyotrophic lateral sclerosis-linked mutation in D-amino acid oxidase are mediated by D-serine.
abstract: Amyotrophic lateral sclerosis is a neuromuscular disease characterized by selective loss of motor neurons leading to fatal paralysis. We previously reported a coding mutation in D-amino acid oxidase (R199W DAO) associated with familial amyotrophic lateral sclerosis. DAO metabolizes D-serine, a co-agonist at the N-methyl-D-aspartic acid receptor. We investigated the mechanisms mediating the pathogenic effects of R199W DAO on motor neuron survival and showed that expression of glial R199W DAO is sufficient to induce apoptosis in cocultured motor neurons and this is sensitive to 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, an N-methyl-d-aspartic acid receptor antagonist selective for the D-serine/glycine site. R199W DAO activates protein aggregation and autophagy, which is also sensitive to this antagonist. Using immunocytochemistry, we showed that D-serine and DAO were abundant in spinal cord motor neurons and depleted in amyotrophic lateral sclerosis. In summary, the toxic effects of R199W DAO on motor neurons can be mediated directly by expression in motor neurons or by astrocytes in coculture, R199W DAO promotes autophagy and its pathogenic effects are at least in part mediated via the N-methyl-d-aspartic acid receptor.
authors.affiliation: Neurogenetics Group, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: Praveen
authors.initials: P
authors.lastname: Paul
authors.affiliation: Neurogenetics Group, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: Tytus
authors.initials: T
authors.lastname: Murphy
authors.affiliation: Neurogenetics Group, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: Zainab
authors.initials: Z
authors.lastname: Oseni
authors.affiliation: Neurogenetics Group, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: Suganthinie
authors.initials: S
authors.lastname: Sivalokanathan
authors.affiliation: Neurogenetics Group, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK. Electronic address: j.belleroche@imperial.ac.uk.
authors.forename: Jacqueline S
authors.initials: JS
authors.lastname: de Belleroche
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001253:Astrocytes; D001343:Autophagy / Q000235:genetics; D002478:Cells, Cultured; D003605:D-Amino-Acid Oxidase / Q000235:genetics* / Q000502:physiology / Q000633:toxicity; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009457:Neuroglia / Q000473:pathology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000502:physiology; D012694:Serine / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D003605:D-Amino-Acid Oxidase
keywords: Amyotrophic lateral sclerosis; Apoptosis; Autophagy; D-amino acid oxidase; D-serine; Motor neurons; N-methyl-D-aspartate receptors