title: Experimental approaches for elucidating co-agonist regulation of NMDA receptor in motor neurons: Therapeutic implications for amyotrophic lateral sclerosis (ALS).
abstract: Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterised by selective loss of motor neurons leading to fatal paralysis. Although most cases are sporadic, approximately 10% of cases are familial and the identification of mutations in these kindred has greatly accelerated our understanding of disease mechanisms. To date, the causal genes in over 70% of these families have been identified. Recently, we reported a mutation (R199W) in the enzyme that degrades d-serine, D-amino acid oxidase (DAO) and co-segregates with disease in familial ALS. Moreover, D-serine and DAO are abundant in human spinal cord and severely depleted in ALS. Using cell culture models, we have defined the effects of R199W-DAO, and shown that it activates autophagy, leads to the formation of ubiquitinated protein aggregates and promotes apoptosis, all of which processes are attenuated by a D-serine/glycine site antagonist of the N-methyl D-aspartate receptor (NMDAR). These findings suggest that the toxic effects of R199W-DAO are at least in part mediated via the NMDAR involving the D-serine/glycine site and that an excitotoxic mechanism may contribute to disease pathogenesis.
authors.affiliation: Neurogenetics Group, Division of Brain Sciences, Department of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Praveen
authors.initials: P
authors.lastname: Paul
authors.affiliation: Neurogenetics Group, Division of Brain Sciences, Department of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. Electronic address: j.belleroche@imperial.ac.uk.
authors.forename: Jackie
authors.initials: J
authors.lastname: de Belleroche
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003605:D-Amino-Acid Oxidase / Q000235:genetics / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000502:physiology; D012694:Serine / Q000235:genetics / Q000378:metabolism
chemical_list: D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D003605:D-Amino-Acid Oxidase
keywords: Amyotrophic lateral sclerosis (ALS); Glycine; Motor neurons; d-Amino acid oxidase (DAO); d-Serine