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2007 Fiscal Year Final Research Report Summary

Molecular pathogenesis of congenital muscular dystrophies and development of new therapeutic measures

Research Project

Project/Area Number 16390256
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionTeikyo University

Principal Investigator

SHIMIZU Teruo  Teikyo University, School of Medicine, Professor (00107666)

Co-Investigator(Kenkyū-buntansha) MATSUMURA Kiichiro  Teikyo University, School of Medicine, Associate Professor (50260922)
SAITO Fumiaki  Teikyo University, School of Medicine, Assistant Professor (40286993)
Project Period (FY) 2004 – 2007
Keywordsα-dystroglycan / α-dystroglycanopathy / laminin / protein convertase / Large / fukutin / congenital muscular dystrophy
Research Abstract

Dystroglycan (DG) links the extracellular matrix with cytoskeleton. Recently, mutations of the genes encoding putative glycosyltransferases were identified in several congenital muscular dystrophies and aberrant glycosylation of α-DG has been implicated in their pathogeneses (α-dystroglycanopathy). In this study, we have obtained several novel findings concerning the molecular pathogenesis of a-dystroglycanopathy.
(1) We found the protease activity that degrades the extracellular domain of β-DG specifically. This activity was suppressed by the inhibitor of MMP-2 and MMP-9. Cultured cells secreted MMP-2 and MMP-9 into the culture medium. Active MMP-2 and MMP-9 enzymes degraded the β-DG. MMP-2 and MMP-9 were activated in Duchenne muscular dystrophy and sarcoglycanopathyas well as in their model animals. These results indicate that inhibitors of MMP-2 and MMP-9 may be effective for these diseases.
(2) Peripheral nerve myelination was defective in the fukutin-deficient chimeric mice, a mouse … More model of Fukuyama-type congenital muscular dystrophy. The density of myelinated nerve fibers was significantly decreased and clusters of abnormally large non-myelinated axons were ensheathed by a single Schwann cell. The sugar chain moiety and laminin-binding activity of α-DG were severely reduced in the peripheral nerve of the chimeric mice. The clustering of acetylcholine receptor was defective and neuromuscular junctions are fragmented in appearance in these mice. These results demonstrate that dysmyelination of peripheral nerve should be carefully watched in congenital muscular dystrophies.
(3) We found the cleavage and secretion of the N-terminal domain of α-DG (α-DG-N). Secreted α-DG-N was both N- and 0-glycosylated.α-DG-N was detectable in the human serum and cerebrospinal fluid. These observations indicate that the cleavage of α-DG-N is a widespread event and suggest that the secreted α-DG-N might be transported via systemic circulation and that the level of α-DG-N may be altered in α-dystroglycanopathies. Less

  • Research Products

    (26 results)

All 2008 2007 2006 2005 2004

All Journal Article (14 results) (of which Peer Reviewed: 7 results) Presentation (12 results)

  • [Journal Article] Processing and secretion of the N-terminal domain of α-dystroglycan in cell culture media2008

    • Author(s)
      Saito F.
    • Journal Title

      F.E.B.S.Lett. 582

      Pages: 439-444

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Processing and secretion of the N-terminal domain of a -dystroglycan in cell culture media2008

    • Author(s)
      Saito, F
    • Journal Title

      F. E. B. S. Lett 582

      Pages: 439-444

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Defective peripheral nerve myelination and neuromuscular junction formation in fukutin-deficient chimeric mice2007

    • Author(s)
      Saito F.
    • Journal Title

      J.Neurochem. 101

      Pages: 1712-1722

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Defective peripheral nerve myelination and neuromuscular junction formation in fukutin-deficient chimeric mice2007

    • Author(s)
      Saito, F
    • Journal Title

      J. Neurochem 101

      Pages: 1712-1722

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Characterization of the protease activity that cleaves the extracellular domain of β-dystroglycan2006

    • Author(s)
      Zhong D.
    • Journal Title

      Biochem.Biophys.Res.Comm. 345

      Pages: 867-871

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Characterization of the protease activity that cleaves the extracellular domain of β -dystroglycan2006

    • Author(s)
      Zhong, D
    • Journal Title

      Biochem. Biophys. Res. Comm 345

      Pages: 867-871

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Proteolysis of β-dystroglycan in muscular diseases2005

    • Author(s)
      Matsumura K.
    • Journal Title

      Neuromusc.Disord. 15

      Pages: 336-341

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Aberrant glycosylation of α-dystroglycan causes defective binding of laminin in the muscle of chicken muscular dystrophy2005

    • Author(s)
      Saito F.
    • Journal Title

      F.E.B.S.Lett. 579

      Pages: 2359-2363

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Characterization of glial cell line-derived neurotrophic factor family receptor α-1 in the peripheral nerve Schwann cells2005

    • Author(s)
      Hase A.
    • Journal Title

      J.Neurochem. 95

      Pages: 537-543

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Proteolysis of ie -dystroglycan in muscular diseases2005

    • Author(s)
      Matsumura, K
    • Journal Title

      Neuromusc. Disord 15

      Pages: 336-341

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Aberrant glycosylation of a -dystroglycan causes defective binding of laminin in the muscle of chicken muscular dystrophy2005

    • Author(s)
      Saito, F
    • Journal Title

      F. E. B. S. Lett 579

      Pages: 2359-2363

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Characterization of glial cell line-derived neurotrophic factor family receptor a -1 in the peripheral nerve Schwann cells2005

    • Author(s)
      Hase, A
    • Journal Title

      J. Neurochem 95

      Pages: 537-543

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] A Japanese patient with distal myopathy with rimmed vacuoles:Missense mutations in the epimerase domain of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene accompanied by hyposialy lation of skeletal muscle glycoproteins2004

    • Author(s)
      Saito F.
    • Journal Title

      Neuromusc.Disord. 14

      Pages: 158-161

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] A Japanese patient with distal myopathy with rimmed vacuoles : Missense mutations in the epimerase domain of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene accompanied by hyposialylation of skeletal muscle glycoproteins2004

    • Author(s)
      Saito, F
    • Journal Title

      Neuromusc. Disord 14

      Pages: 158-161

    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] 脳脊髄液におけるdystroglycanプロセッシング断片の発現2007

    • Author(s)
      新井 祐子
    • Organizer
      第48回日本神経学会総会
    • Place of Presentation
      名古屋
    • Year and Date
      20070500
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Processing and secretion of a -dystroglycan in human cerebrospinal fluid2007

    • Author(s)
      Arai, Y
    • Organizer
      The 48th Annual Meeting of the Japanese Society of Neurology
    • Place of Presentation
      Nagoya
    • Year and Date
      20070500
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Matrix metalloproteinaseによるβdystroglycanの分解2006

    • Author(s)
      松村 喜一郎
    • Organizer
      第47回日本神経学会総会
    • Place of Presentation
      東京
    • Year and Date
      20060500
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] αDystroglycanopathyにおける神経筋障害の検討2006

    • Author(s)
      斉藤 史明
    • Organizer
      第47回日本神経学会総会
    • Place of Presentation
      東京
    • Year and Date
      20060500
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Oculodentodigital dysplasiaにおけるGJA1遺伝子異常の解析2006

    • Author(s)
      齋藤 祐子
    • Organizer
      第47回日本神経学会総会
    • Place of Presentation
      東京
    • Year and Date
      20060500
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] 末梢神経,シュワン細胞におけるGDNF受容体(GFRα-1)の発現解析2006

    • Author(s)
      小林 麻子
    • Organizer
      第47回日本神経学会総会
    • Place of Presentation
      東京
    • Year and Date
      20060500
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Proteolysis of β-dystroglycan by matrix metalloproteinase2006

    • Author(s)
      Matsumura, K
    • Organizer
      The 47th Annual Meeting of the Japanese Society of Neurology
    • Place of Presentation
      Tokyo
    • Year and Date
      20060500
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Analysis of neuromuscular involvement in a -dystroglycanopathy2006

    • Author(s)
      Saito, F
    • Organizer
      The 47th Annual Meeting of the Japanese Society of Neurology
    • Place of Presentation
      Tokyo
    • Year and Date
      20060500
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Analysis of GJA1 gene defects in Oculodentodigital dysplasia2006

    • Author(s)
      Saito, Y
    • Organizer
      The 47th Annual Meeting of the Japanese Society of Neurology
    • Place of Presentation
      Tokyo
    • Year and Date
      20060500
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] Expression of GFR a -1 in peripheral nerve and Schwann cells2006

    • Author(s)
      Kobayashi, A
    • Organizer
      The 47th Annual Meeting of the Japanese Society of Neurology
    • Place of Presentation
      Tokyo
    • Year and Date
      20060500
    • Description
      「研究成果報告書概要(欧文)」より
  • [Presentation] 筋疾患におけるβdystroglycanのmatrix metalloproteinaseによる分解2005

    • Author(s)
      新井 謙
    • Organizer
      第46回日本神経学会総会
    • Place of Presentation
      鹿児島
    • Year and Date
      20050500
    • Description
      「研究成果報告書概要(和文)」より
  • [Presentation] Proteolysis of β-dystroglycan by matrix metalloproteinase in muscular diseases2005

    • Author(s)
      Arai, K
    • Organizer
      The 46th Annual Meeting of the Japanese Society of Neurology
    • Place of Presentation
      Kagoshima
    • Year and Date
      20050500
    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2010-02-04  

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