| Project/Area Number |
24500472
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Neurophysiology and muscle physiology
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| Research Institution | National Center of Neurology and Psychiatry |
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Principal Investigator |
IMAMURA Michihiro 独立行政法人国立精神・神経医療研究センター, 神経研究所 遺伝子疾患治療研究部, 室長 (80221787)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEDA Shin'ichi 独立行政法人国立精神・神経医療研究センター神経研究所, 遺伝子疾患治療研究部, 部長 (90171644)
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 筋ジストロフィー / 実験動物 / 遺伝子疾患 / WWP1 E3 ユビキチンリガーゼ / タンパク質分解 / WWP1 / E3ユビキチンリガーゼ / ミスセンス変異 / 筋形質膜 / 筋小胞 / ミトコンドリア / HECT型E3ユビキチンリガーゼ / ジストログリカン / サルコグリカン / 骨格筋 / HECTドメイン / WWドメイン |
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| Outline of Final Research Achievements |
The R441Q missense mutation in the WWP1 protein was reported as the most promising candidate responsible for chicken muscular dystrophy (MD). We generated an antibody against WWP1, and characterized WWP1 protein expression in skeletal muscles in vivo and in vitro. In wild-type skeletal muscle, WWP1 was detected as an approximately 130-kDa protein and localized to the sarcolemma, sarcoplasmic reticulum, mitochondria, as well as in a part of the nucleus, whereas it was markedly degraded and absent from the sarcolemma in MD muscle. These changes were already observed in MD chickens in the pre-pathological stage. In vitro expression analysis demonstrated significant degradation of mutant but not wild-type WWP1, specifically in myogenic cells. Our study revealed that the R441Q missense mutation in the WWP1 protein causes its degradation as well as loss of its sarcolemmal localization, which are hence implicated in the pathogenesis of chicken MD.
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