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Defect of peroxisome metabolism impairs development of central nervous system

Research Project

Project/Area Number 17K15621
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Pathological medical chemistry
Research InstitutionKyushu University

Principal Investigator

Abe Yuichi  九州大学, 生体防御医学研究所, 学術研究員 (00529092)

Research Collaborator Fujiki Yukio  
Honsho Masanori  
Yamashita Toshihide  
Ohgi Ryohei  
Project Period (FY) 2017-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsペルオキシソーム / ペルオキシソーム形成異常症 / 小脳 / プルキンエ細胞 / 代謝障害 / 転写調節 / 脳神経疾患 / オルガネラ
Outline of Final Research Achievements

Peroxisome is a subcellular organelle essential for various metabolic reactions. Peroxisome biogenesis disorders (PBDs) manifest as neurological deficits in the brain, including abnormal cerebellum development. However, the mechanisms underlying pathogenesis remain enigmatic. In this research, we showed that ERK and AKT signaling are attenuated in peroxisome-deficient mouse by an elevated level of brain-derived neurotrophic factor (BDNF) together with the enhanced expression of TrkB-T1, a dominant-negative isoform of the BDNF receptor. This result suggests that dysregulation of the BDNF-TrkB pathway, an essential signaling for cerebellar morphogenesis, gives rise to the pathogenesis of cerebellum in PBDs. In addition, we revealed that the elevation of BDNF was induced by the cytosolic reductive state caused by the mislocalized catalase in peroxisome-deficient glia cells. Thus, our findings demonstrate for the first time the pathogenesis of PBDs.

Academic Significance and Societal Importance of the Research Achievements

これまで、ペルオキシソーム形成異常症の病態発症機構に関して、分子レベルでの解明には至っていなかった。そんななか、我々の研究成果はBDNF-TrkBシグナル伝達系の異常が小脳形態異常の原因の一つであることを示し、世界で初めてペルオキシソーム形成異常症の病態発症機構を分子レベルで解明することに漕ぎ着けた。さらに、ペルオキシソーム欠損により誘発される細胞質還元化が及ぼす細胞機能への影響に関しても世界で初めての発見である。これらの成果は根本的な治療法が確立されていないペルオキシソーム形成異常症の治療法開発に繋がる可能性が高い。

Report

(3 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • Research Products

    (8 results)

All 2019 2018 2017 Other

All Journal Article (4 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (3 results) (of which Int'l Joint Research: 1 results) Remarks (1 results)

  • [Journal Article] Dynamics of the nucleoside diphosphate kinase protein DYNAMO2 correlates with the changes in the global GTP level during the cell cycle of <i>Cyanidioschyzon merolae</i>2019

    • Author(s)
      Imoto, Y., Abe, Y., Okumoto, K., Ohnuma, M., Kuroiwa, H., Kuroiwa, T., and Fujiki, Y.
    • Journal Title

      Proceedings of the Japan Academy, Series B

      Volume: 95 Issue: 2 Pages: 75-85

    • DOI

      10.2183/pjab.95.007

    • NAID

      130007591938

    • ISSN
      0386-2208, 1349-2896
    • Year and Date
      2019-02-08
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A newly identified mutation in the PEX26 gene is associated with a milder form of Zellweger spectrum disorder.2019

    • Author(s)
      Tanaka, A. J., Okumoto, K., Tamura, S., Abe, Y., Hirsch, Y., Deng, L., Ekstein, J., Chung, W. K., and Fujiki Y.
    • Journal Title

      Cold Spring Harb. Mol. Case Stud.

      Volume: 5 Issue: 1 Pages: 1-16

    • DOI

      10.1101/mcs.a003483

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Onsite GTP fuelling via DYNAMO1 drives division of mitochondria and peroxisomes2018

    • Author(s)
      Imoto Yuuta、Abe Yuichi、Honsho Masanori、Okumoto Kanji、Ohnuma Mio、Kuroiwa Haruko、Kuroiwa Tsuneyoshi、Fujiki Yukio
    • Journal Title

      Nature Communications

      Volume: 9 Issue: 1 Pages: 1-12

    • DOI

      10.1038/s41467-018-07009-z

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Peroxisome biogenesis deficiency attenuates the BDNF-TrkB pathway-mediated development of the cerebellum2018

    • Author(s)
      Abe Yuichi、Honsho Masanori、Itoh Ryota、Kawaguchi Ryoko、Fujitani Masashi、Fujiwara Kazushirou、Hirokane Masaaki、Matsuzaki Takashi、Nakayama Keiko、Ohgi Ryohei、Marutani Toshihiro、Nakayama Keiichi I、Yamashita Toshihide、Fujiki Yukio
    • Journal Title

      Life Science Alliance

      Volume: 1 Issue: 6 Pages: 1-17

    • DOI

      10.26508/lsa.201800062

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Pathogenesis mechanism of peroxisome biogenesis disorders2019

    • Author(s)
      Yuichi Abe, Masanori Honsho, Ryota Itoh, Ryoko Kawaguchi, Masashi Fujitani, Kazushirou Fujiwara, Masaaki Hirokane, Takashi Matsuzaki, Keiko Nakayama, Ryohei Ohgi, Toshihiro Marutani, Keiichi I. Nakayama, Toshihide Yamashita, and Yukio Fujiki
    • Organizer
      EMBO Workshop “Current advances in protein translocation across membranes”
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Pex14欠損マウスにおける小脳形態異常の分子機構2018

    • Author(s)
      阿部雄一, 本庄雅則, 藤木幸夫
    • Organizer
      平成30年度日本生化学会九州支部例会
    • Related Report
      2018 Annual Research Report
  • [Presentation] PEX14障害マウスにおける小脳形態異常2017

    • Author(s)
      阿部雄一、本庄雅則、大城遼平、藤木幸夫
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report
  • [Remarks] 世界初、ペルオキシソーム形成異常症の発症メカニズムを解明 - 治療法開発にも期待 -

    • URL

      http://www.kyushu-u.ac.jp/ja/researches/view/302

    • Related Report
      2018 Annual Research Report

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Published: 2017-04-28   Modified: 2020-03-30  

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