2006 Fiscal Year Final Research Report Summary
Research on molecular pathogenesis of congenital muscular dystrophy -Characterization of the intra-/extra-cellular interaction of dystroglycan-
| Project/Area Number |
17590898
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Teikyo University |
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Principal Investigator |
SAITO Fumiaki Teikyo University, School of Medicine, Research Associate, 医学部, 助手 (40286993)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Muscular dystrophy / Dystroglycan / Glycosylation / Fukutin / Neuromuscular junction / Laminin / Agrin |
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| Research Abstract |
To clarify the molecular mechanisms underlying congenital muscular dystrophy, I characterized the skeletal muscle, neuromuscular junction and peripheral nerve of dystrophic chicken and fukutin deficient chimeric mouse, animal models of congenital muscular dystrophy. First, analysis using dystrophic chicken revealed that 1) glycosylation of α-dystroglycan is defective and its laminin binding activity is reduced in the skeletal muscle of dystrophic chicken, 2) two distinct molecular species of α-dystroglycan exists in the chicken and the smaller species doesn't possess the laminin binding activity, 3) amount of Galβ1-3GalNAc moiety is increased whereas Siaa2-3Gal is reduced on α-dystroglycan of the dystrophic chicken as compared to control 4) expression of β1-integron is up-regulated in the skeletal muscle and heart of the chicken. Second, experiments with fukutin deficient chimeric mice demonstrated that 1) neuromuscular junction of the chimeric mice is small and fragmented in appearance, 2) agrin binding activity and its expression is reduced in the chimeric neuromuscular junction, 3) the radial sorting mechanism of peripheral nerve axon is defective and myelinated fiber is decreased in the chimeric mice, 4) α-dystroglycan is aberrantly glycosylated and its laminin binding activity is decreased in the chimeric nerve. In addition, by yeast two-hybrid screening of human cDNA library, I cloned plasma membrane Ca^<2+> ATPase as a potential binding protein of β-dystroglycan. However, the molecular interaction of these proteins was not confirmed at protein level with co-immunoprecipitation experiments or pull-down assays, suggesting that the interaction is so weak that these methodology couldn't detect the binding.
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