title: Neuregulin 1 confers neuroprotection in SOD1-linked amyotrophic lateral sclerosis mice via restoration of C-boutons of spinal motor neurons.
abstract: BACKGROUND
  Increasing evidence implicates the role of the cell types surrounding motor neurons, such as interneurons and glial cells, in non-cell autonomous neurodegeneration of amyotrophic lateral sclerosis (ALS). C-boutons, the large cholinergic synapses that innervate spinal α-motor neurons to control their excitability, are progressively lost from motor neurons in both human ALS and mutant Cu/Zn superoxide dismutase 1 (SOD1)-ALS mice. Neuregulin-1 (NRG1), a trophic factor implicated in neural development, transmission, and synaptic plasticity, has been reported to localize in the synapse of C-boutons. However, the roles of NRG1 in maintenance of motor neuron health and activity, as well as the functional consequences of its alteration in motor neuron disease, are not fully understood.
  
  
  RESULTS
  NRG1 was localized to the post-synaptic face of C-boutons and its expression was significantly lost in SOD1-ALS mice and human ALS patients. Losses of NRG1 expression and C-boutons occurred almost contemporaneously in SOD1-ALS mice. In addition, expressions of ErbB3 and ErbB4, receptors for NRG1, were reduced in the motor neurons of SOD1-ALS mice. Furthermore, viral-mediated delivery of type III-NRG1 to the spinal cord restored the number of C-boutons and extended the survival time of SOD1-ALS mice.
  
  
  CONCLUSIONS
  These results suggest that maintenance of NRG1-ErbB4/3 axis by supplementation of NRG1 confers neuroprotection in motor neuron disease, partly through the maintenance of C-boutons of spinal motor neurons.
authors.affiliation: Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama, 3510198, Japan.
authors.forename: Jurate
authors.initials: J
authors.lastname: Lasiene
authors.affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 4648601, Japan.
authors.forename: Okiru
authors.initials: O
authors.lastname: Komine
authors.affiliation: Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama, 3510198, Japan.|Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Saitama, 3510198, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Fujimori-Tonou
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA, 98104, USA.|Ionis Pharmaceuticals, Inc., Carlsbad, CA, 92010, USA.
authors.forename: Berit
authors.initials: B
authors.lastname: Powers
authors.affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 4648601, Japan.
authors.forename: Fumito
authors.initials: F
authors.lastname: Endo
authors.affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 4648601, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 4648601, Japan.
authors.forename: Jin
authors.initials: J
authors.lastname: Shijie
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA.
authors.forename: John
authors.initials: J
authors.lastname: Ravits
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA, 98104, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Horner
authors.affiliation: Division of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo, 1058512, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Misawa
authors.affiliation: Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama, 3510198, Japan. kojiyama@riem.nagoya-u.ac.jp.|Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 4648601, Japan. kojiyama@riem.nagoya-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism*; D000066829:Neuroprotection / Q000502:physiology*; D011180:Postmortem Changes; D017729:Presynaptic Terminals / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D051669:Shab Potassium Channels / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; C000606290:SOD1 protein, human; D051669:Shab Potassium Channels; C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3