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Molecular characterization of a HECT-type E3 ubiquitin ligase that is encoded in the WWP1 gene responsible for chicken muscular dystrophy.

Research Project

Project/Area Number 24500472
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurophysiology and muscle physiology
Research InstitutionNational Center of Neurology and Psychiatry

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)

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)
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
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)
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
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.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (14 results)

All 2015 2014 2013 2012 Other

All Journal Article (9 results) (of which Peer Reviewed: 9 results,  Open Access: 3 results) Presentation (5 results)

  • [Journal Article] Low intensity training of mdx mice reduces carbonylation and increases expression levels of proteins involved in energy metabolism and muscle contraction.2015

    • Author(s)
      Hyzewicz J, Tanihata J, Kuraoka M, Ito N, Miyagoe-Suzuki Y, Takeda S
    • Journal Title

      Free Radic Biol Med

      Volume: 82 Pages: 122-136

    • DOI

      10.1016/j.freeradbiomed.2015.01.023

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fukutin is prerequisite to ameliorate muscular dystrophic phenotype by myofiber-selective LARGE expression.2015

    • Author(s)
      Ohtsuka Y, Kanagawa M, Yu CC, Ito C, Chiyo T, Kobayashi K, Okada T, Takeda S’I, Toda T.
    • Journal Title

      Sci Rep

      Volume: 5 Issue: 1 Pages: 8316-8316

    • DOI

      10.1038/srep08316

    • NAID

      120005600773

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] α1-Syntrophin deficient mice exhibit impaired muscle force recovery after osmotic shock.2014

    • Author(s)
      Yokota T, Miyagoe-Suzuki Y, Ikemoto T, Matsuda R, Takeda S
    • Journal Title

      Muscle Nerve

      Volume: 49 Issue: 5 Pages: 728-735

    • DOI

      10.1002/mus.23990

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction2014

    • Author(s)
      Sumimasa Arimura, Takashi Okada, Tohru Tezuka, Tomoko Chiyo, Yuko Kasahara, Toshiro Yoshimura, Masakatsu Motomura, Nobuaki Yoshida, David Beeson, Shin’ichi Takeda, Yuji Yamanashi
    • Journal Title

      Science

      Volume: 345 Issue: 6203 Pages: 1505-1508

    • DOI

      10.1126/science.1250744

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Initial Pulmonary Respiration Causes Massive Diaphragm Damage and Hyper-CKemia in Duchenne Muscular Dystrophy Dog2013

    • Author(s)
      Nakamura A, Kobayashi M, Kuraoka M, Yuasa K, Yugeta N, Okada T, Takeda S
    • Journal Title

      Sci Rep

      Volume: 3 Issue: 1 Pages: 2183-2183

    • DOI

      10.1038/srep02183

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Highly efficient in vivo delivery of PMO into regenerating myotubes and rescue in laminin-α2 chain-null congenital muscular dystrophy mice2013

    • Author(s)
      Aoki Y, Nagata T, Yokota T, Nakamura A, Wood MJ, Partridge T, Takeda S
    • Journal Title

      Hum Mol Genet

      Volume: 22 Issue: 24 Pages: 4914-4928

    • DOI

      10.1093/hmg/ddt341

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Prednisolone improves walking in Japanese Duchenne muscular dystrophy patients2013

    • Author(s)
      Takeuchi F, Yonemoto N, Nakamura H, Shimizu R, Komaki H, Mori-Yoshimura M, Hayashi YK, Nishino I, Kawai M, Kimura E, Takeda S
    • Journal Title

      J Neurol

      Volume: 260 Issue: 12 Pages: 3023-3029

    • DOI

      10.1007/s00415-013-7104-y

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Demonstration of systemic exon 45-55 multiple skipping in dystrophic mdx52 mice2012

    • Author(s)
      Aoki Y, Yokota T, Nagata T, Nakamura A, Nagaraju K, Hoffman E, Partridge T, Takeda S.
    • Journal Title

      Proc Natl Acad Sci USA

      Volume: 109 Issue: 34 Pages: 13763-13768

    • DOI

      10.1073/pnas.1204638109

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Extensive and prolonged restoration of dystrophin expression with vivo-morpholino-mediated multiple exon skipping in dystrophic dogs.2012

    • Author(s)
      Yokota T, Nakamura A, Saito T, Nagata T, Partridge T, Hoffman E, Takeda S.
    • Journal Title

      Nucleic Acid Ther

      Volume: 22 Issue: 5 Pages: 306-315

    • DOI

      10.1089/nat.2012.0368

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Presentation] Differences in Degradation and Distribution of Mutated WP1 E3 Ubiquitin Protein Ligase between Chicken and Mouse Skeletal Muscles2014

    • Author(s)
      Imamura, M., Takeda, S.
    • Organizer
      American Society for Cell Biology
    • Place of Presentation
      Pennsylvania Convention Center, Philadelphia, PA, U.S.A.
    • Year and Date
      2014-12-06 – 2014-12-10
    • Related Report
      2014 Annual Research Report
  • [Presentation] Analysis of Interaction of WWP1 E3 Ubiquitin Protein Ligase with Dystrophin-Associated Glycoproteins2013

    • Author(s)
      Imamura M, Takeda S
    • Organizer
      53rd American Society for Cell Biology Annual Meeting
    • Place of Presentation
      Ernest N. Morial Convention Center, New Orleans, Louisiana, USA
    • Related Report
      2013 Research-status Report
  • [Presentation] An R441Q mutation of the WWP1 gene causes WWP1 degradation in skeletal muscle of chicken muscular dystrophy2012

    • Author(s)
      Imamura M and Takeda S
    • Organizer
      The American Society for Cell Biology 2012 Annual Meeting
    • Place of Presentation
      Moscone Center, San Francisco , USA
    • Related Report
      2012 Research-status Report
  • [Presentation] Treatment of Muscular Dystrophy

    • Author(s)
      Takeda S
    • Organizer
      The 11th Annual Meeting of the Asian and Oceanian Myology Center
    • Place of Presentation
      Shirankaikan, Kyoto, Japan
    • Related Report
      2012 Research-status Report
  • [Presentation] Gene Therapy for Neuromuscular Disorders

    • Author(s)
      Takeda S
    • Organizer
      Japan Society of Gene Therapy 2012 18th Annual Meeting
    • Place of Presentation
      Hotel Kumamoto Terrsa, Kumamoto, Japan
    • Related Report
      2012 Research-status Report

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Published: 2013-05-31   Modified: 2019-07-29  

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