Analysis of pathogenic roles of MuSK antibodies in myasthenia gravis using the experimental animal models.
| Project/Area Number |
18590946
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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 | Tokyo Metropolitan Institute of Gerontology (2007)
Ehime University (2006) |
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Principal Investigator |
SHIGEMOTO Kazuhiro Tokyo Metropolitan Institute of Gerontology, Tokyo Metropolitan Institute of Gerontology, Research Team for Molecular Biomarkers, Team Leader (40284400)
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| Co-Investigator(Kenkyū-buntansha) |
UEDA Norifumi Tokyo Metropolitan Foundation for Research on aging Promotion Human Welfare, Dept. of Molecular Pathology, Professor (30030886)
MATSUDA Seiji Tokyo Metropolitan Foundation for Research on aging Promotion Human Welfare, Dept. of Anatomy and Embryology, 教授 (40173843)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | MuSK / Myasthenia gravis / Neuromuscular junction / 神経筋シナプス |
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| Research Abstract |
We have provided the evidence that active immunization with MuSK protein reproduces myasthenia gravis in animals. Next we focus on how MuSK antibodies cause MG. The pathogenic roles of MuSK antibodies in MG have been questioned as the number of AChRs is not reduced and complement is not deposited at the NMJ of biceps brachii muscles MuSK-positive patients with MG. The mechanisms of MG caused by AChR antibodies are well delineated, but the revealed mechanisms are not able to simply apply to MG with MuSK antibodies. MuSK antibodies have been identified as predominantly IgG4 subclass, which does not activate complement. We found that agrin-induced clustering of AChR was strongly blocked in the presence of MuSK antibodies, whereas absorption of the antibodies with purified MuSK products prevented this blocking effect. These results showed that the MuSK antibodies effectively inhibited the formation of agrin-induced AChR clustering. Intriguingly, the monovalent Fab fragments of MuSK antibodies from rabbits with EAMG also inhibited AChR clustering by agrin on C2C12 cells, indicating that complement-mediated mechanisms are not necessarily required for such inhibition. We then examined the reduced expression of AChR at NMJ in soleus muscles of paretic and normal rabbits by fluorescence microscopy. In addition, the structure of NMJ in our paretic rabbits, as well as the size and branching of the motor terminals, were significantly reduced. Electron microscopic observations of NMJ in rabbits with EAMG induced by injection of MuSK protein demonstrated a significant loss of complexity of convoluted synaptic folds but no destruction, and EAMG model cited here resembles the phenotype of humans with MG and MuSK antibodies. Our results showed that MuSK antibodies inhibit both anterograde and retrograde signals required for maintaining the synaptic structures in mature NMJ.
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Report
(3 results)
Research Products
(27 results)
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[Journal Article] Induction of myasthenia by immunization against muscle-specific kinase.2006
Author(s)
Shigemoto K, Kubo S, Maruyama N, Hato N., Yamada T, Jie C, Kobayashi N, Mominoki K, Abe Y, Ueda N, & Matsuda S.
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Journal Title
J Clin Invest 116(4)
Pages: 1016-1024
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Induction of myasthenia by immunization against muscle-specific kinase.2006
Author(s)
K.Shigemoto, S.Kubo, N.Maruyama, N.Hato, T.Yamada, C.Jie, N.Kobayashi, K.Mominoki, Y.Abe, N.Ueda, S.Matsuda.
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Journal Title
J Clin Invest 116(4)
Pages: 1016-1024
Related Report
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[Journal Article] A Small Ras-like protein Ray/Rab1c modulates the p53-regulating activity of PRPK.2006
Author(s)
Y.Abe, T.Takeuchi, Y.Imai, R.Murase, Y.Kamei, T.Fujibuchi, S.Matsumoto, N.Ueda, M.Ogasawara, K.Shigemoto, K.Kito
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Journal Title
Biochem Biophys Res Commun 344(1)
Pages: 377-385
Related Report
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