title: Deleterious effects of lymphocytes at the early stage of neurodegeneration in an animal model of amyotrophic lateral sclerosis.
abstract: BACKGROUND
  Non-neuronal cells, such as microglia and lymphocytes, are thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Previous studies have demonstrated neuroprotective effects of lymphocytes at the end stage of ALS, partly through induction of alternatively activated microglia (M2 microglia), which are neuroprotective. In this study, we investigated the role of lymphocytes in the early stage of the disease using an animal model of inherited ALS.
  
  
  METHODS
  We established a transgenic mouse line overexpressing the familial ALS-associated G93A-SOD1 mutation (harboring a single amino acid substitution of glycine to alanine at codon 93) with depletion of the Rag2 gene (mSOD1/RAG2-/- mice), an animal model of inherited ALS lacking mature lymphocytes. Body weights, clinical scores and motor performance (hanging wire test) of mSOD1/RAG2-/- mice were compared to those of mutant human SOD1 transgenic mice (mSOD1/RAG2+/+ mice). Activation of glial cells in the spinal cords of these mice was determined immunohistochemically, and the expression of mRNA for various inflammatory and anti-inflammatory molecules was evaluated.
  
  
  RESULTS
  Clinical onset in mSOD1/RAG2-/- mice was significantly delayed, and the number of lectin-positive cells in spinal cord was increased at the early stage of disease when compared to mSOD1/RAG2+/+ mice. Quantitative RT-PCR confirmed that mRNA for Ym1, an M2 microglial-related molecule, was significantly increased in mSOD1/RAG2-/- mouse spinal cords at the early disease stage.
  
  
  CONCLUSIONS
  Compared with mSOD1/RAG2+/+ mice, mSOD1/RAG2-/- mice displayed delayed onset and increased M2 microglial activation at the early stage of disease. Thus, lymphocytes at the early pathological phase of ALS display a deleterious effect via inhibition of M2 microglial activation.
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Tada
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Okuno
authors.forename: Teruhito
authors.initials: T
authors.lastname: Yasui
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakatsuji
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Sugimoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kikutani
authors.forename: Saburo
authors.initials: S
authors.lastname: Sakoda
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D037102:Lectins / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D009410:Nerve Degeneration / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D037102:Lectins; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases