title: Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis is a devastating neurodegenerative disorder characterized by the progressive loss of spinal motor neurons. While the aetiological mechanisms underlying the disease remain poorly understood, oxidative stress is a central component of amyotrophic lateral sclerosis and contributes to motor neuron injury. Recently, oxidation resistance 1 (OXR1) has emerged as a critical regulator of neuronal survival in response to oxidative stress, and is upregulated in the spinal cord of patients with amyotrophic lateral sclerosis. Here, we tested the hypothesis that OXR1 is a key neuroprotective factor during amyotrophic lateral sclerosis pathogenesis by crossing a new transgenic mouse line that overexpresses OXR1 in neurons with the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Interestingly, we report that overexpression of OXR1 significantly extends survival, improves motor deficits, and delays pathology in the spinal cord and in muscles of SOD1(G93A) mice. Furthermore, we find that overexpression of OXR1 in neurons significantly delays non-cell-autonomous neuroinflammatory response, classic complement system activation, and STAT3 activation through transcriptomic analysis of spinal cords of SOD1(G93A) mice. Taken together, these data identify OXR1 as the first neuron-specific antioxidant modulator of pathogenesis and disease progression in SOD1-mediated amyotrophic lateral sclerosis, and suggest that OXR1 may serve as a novel target for future therapeutic strategies.
authors.affiliation: 1 Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3QX, UK.
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Liu
authors.affiliation: 1 Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3QX, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Edwards
authors.affiliation: 1 Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3QX, UK.
authors.forename: Sheena
authors.initials: S
authors.lastname: Lee
authors.affiliation: 1 Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3QX, UK.
authors.forename: Mattéa J
authors.initials: MJ
authors.lastname: Finelli
authors.affiliation: 2 Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Davies
authors.affiliation: 1 Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3QX, UK peter.oliver@dpag.ox.ac.uk kay.davies@dpag.ox.ac.uk.
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
authors.affiliation: 1 Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3QX, UK peter.oliver@dpag.ox.ac.uk kay.davies@dpag.ox.ac.uk.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Oliver
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000627:therapeutic use; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000276:immunology
chemical_list: D000975:Antioxidants; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; C423572:Oxr1 protein, mouse
keywords: ALS; inflammation; motor neuron disease; neurodegeneration; oxidative stress