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Motor neuron-selective cytotoxicity caused by ALS-linked mutant SOD1 proteins

Research Project

Project/Area Number 17590907
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionNational Institute of Neuroscience, NCNP

Principal Investigator

TATENO Minako  National Inst. of Neuroscience, Peripheral Nervous System Research, Assistant Director, 神経研究所疾病研究第五部, 室長 (50332325)

Co-Investigator(Kenkyū-buntansha) ARAKI Toshiyuki  National Inst. of Neuroscience, Peripheral Nervous System Research, Director, 神経研究所疾病研究第五部, 部長 (70263275)
TAKAHASHI Ryosuke  Kyoto Univ, Neurology, Professor, 医学部, 教授 (90216771)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsNeurodegenerative disease / Neuroscience / ALS / SODl / プロテオーム / 神経変性疾患 / 異常タンパク仮説
Research Abstract

We found that misfolded mutant SOD1 proteins, the products of familial ALS-causative gene, selectively impair a transport of choline aoetyltransferase (ChAT) in spinal motoneurons.
To investigate the reason for motor neuron-specific cytotoxicity of mutant SOD1 proteins, we first isolated toxic species of mutant SOD1 proteins, misfolded species, from spinal cords of G93A SOD1-transgenic mice, the most widely used model mouse for ALS research. Immunoprecipitation analyses revealed that those misfolded SOD1 species were selectively interacted with the molecules responsible for a transport of ChAT. ChAT is a key enzyme for acetylcholine synthesis and needed to be transported within the long axons of spinal motor neurons, since acetylcholine is a major neurotransmitter of those neurons. Actually, the transport rate of ChAT was significantly reduced in motoneuronal axons in G93A SOD1 transgenic mice preceding to disease onset. These data strongly suggest that the decrease of ChAT transport is … More caused by the binding of misfolded mutant SOD1 to the molecules for ChAT transport.
Next, we established a cell line-model system for studying the cytotoxicity of mutant SOD1. NG108-15 cells, hybrid cells of mouse neuroblastoma and rat glioma, can differentiate into cholinergic neuron-like and release acetylcholine in response to KCI stimuli. We introduced wild / mutant SOD1 into these cells and induced their differentiation, and then found that oxidative stress significantly reduce acetylcholine-release in mutant SOD1-transfected cells compared with wt SOD1-transfected cells. Oxidative stress effectively induces a misfolding of mutant SOD1 both in vivo and in vitro. A huge amount of misfolded SOD1 species was detected in mutant SOD1-tranfected cells under oxidative stress, and subpopulation of those misfolded species was interacted with the molecules responsible for ChAT transport.
All these data strongly suggest that misfolded mutant SOD1 proteins sequester the molecules for ChAT transport, leading to a decrease of ChAT transport and a dysfunction of spinal motor neurons. Since most other neurons in spinal cords utilize neurotransmitters except for acetylcholine and do not depend on ChAT, this characteristic of mutant SOD1 would be selectively toxic to spinal motor neurons. Less

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (4 results)

All 2006

All Journal Article (4 results)

  • [Journal Article] SOD1 aggregates within motoneuronal axons do not associate with mito chondria.2006

    • Author(s)
      舘野美成子
    • Journal Title

      International symposium on ALS/MND (学会発表)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Unusually folded SOD1 species sequester specific motor molecules and inhibit the axonal transport of their cargos.2006

    • Author(s)
      Minako Tateno
    • Journal Title

      The 29^<th> Annual meeting of the Japan Neuroscience society

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] SOD1 aggregates within motoneuronal axons do not associate with Mitochondria.2006

    • Author(s)
      Minako Tateno
    • Journal Title

      The 17^<th> International symposium on ALS/MND

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] SOD1 aggregates generated within motoneuronal dendrites/cell bodies move into axons before disease onset in a G93ASOD1 transgenic mouse model.2006

    • Author(s)
      Ryosuke Takahashi
    • Journal Title

      The 17^<th> International symposium on ALS/MND

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary

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Published: 2005-04-01   Modified: 2016-04-21  

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