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Mechanism of reciprocal enhancement of dopamine metabolism and mitochondrial stress-induced neurotoxicity

Research Project

Project/Area Number 17K08302
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pharmacology in pharmacy
Research InstitutionAsahikawa Medical College (2017, 2019-2022)
Hokkaido University (2018)

Principal Investigator

SASAJIMA Hitoshi  旭川医科大学, 医学部, 講師 (00374562)

Project Period (FY) 2017-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords神経変性 / フェロトーシス / ドパミン / ミトコンドリアストレス / 鉄代謝 / 活性酸素 / モノアミン / ミトコンドリア / パーキンソン病 / オートファジー / 神経保護 / ロテノン / ドパミン代謝 / 抗酸化物質 / 薬学 / 神経科学
Outline of Final Research Achievements

Dopaminergic neurons are more vulnerable to mitochondrial stress than other neurons, and their neurodegeneration causes olfactory dysfunction and Parkinson's disease. This study revealed that dopaminergic neurodegeneration, previously thought to be caused by apoptosis, is nonapoptotic, that modulation of dopamine metabolism is effective in suppressing cell death, and that a type of monoamine derivative has potent dopaminergic neuron protective effects. It was also found that this cell death could be inhibited by dopamine synthesis inhibitors, monoamine oxidase inhibitors, iron chelators, and autophagy inhibitors, suggesting the involvement of ferritinophagy, an iron-dependent autophagy in dopaminergic neurodegeneration.

Academic Significance and Societal Importance of the Research Achievements

既存のパーキンソン病の治療では、ドパミン前駆体の投与もしくはドパミン代謝酵素阻害薬の投与により、脳内ドパミン濃度を保つことが主眼となっているが、いわば対症療法に過ぎず、原因であるドパミン神経変性の進行は阻止も遅延もできないため、やがて投薬効果が減少する。そこで次世代パーキンソン病治療に求められる方策は、iPS由来ドパミン神経細胞移植と、ドパミン神経変性阻止と言える。本研究では、ドパミン神経変性阻止方法の新たなプラットフォームとして細胞内鉄動態の調節を提示する。フェリチノファジー誘導感度の調節、あるいは細胞内2価鉄の局在管理により、ドパミン神経変性を未然に防ぐ可能性が示唆される。

Report

(7 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (5 results)

All 2023 2019 2018 2017

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (2 results)

  • [Journal Article] Interaction between PI3K and the VDAC2 channel tethers Ras-PI3K-positive endosomes to mitochondria and promotes endosome maturation2023

    • Author(s)
      Satoh Aya O.、Fujioka Yoichiro、Kashiwagi Sayaka、Yoshida Aiko、Fujioka Mari、Sasajima Hitoshi、Nanbo Asuka、Amano Maho、Ohba Yusuke
    • Journal Title

      Cell Reports

      Volume: 42 Issue: 3 Pages: 112229-112229

    • DOI

      10.1016/j.celrep.2023.112229

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Localization of BCR-ABL to Stress Granules Contributes to Its Oncogenic Function2019

    • Author(s)
      Sayaka Kashiwagi, Yoichiro Fujioka, Takeshi Kondo, Aya O. Satoh, Aiko Yoshida, Mari Fujioka, Hitoshi Sasajima, Maho Amano, Takanori Teshima, Yusuke Ohba
    • Journal Title

      Cell Structure and Function

      Volume: 44 Issue: 2 Pages: 195-204

    • DOI

      10.1247/csf.19033

    • NAID

      130007775561

    • ISSN
      0386-7196, 1347-3700
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Folding Latency of Fluorescent Proteins Affects the Mitochondrial Localization of Fusion Proteins2019

    • Author(s)
      Sayaka Kashiwagi, Yoichiro Fujioka, Aya O. Satoh, Aiko Yoshida, Mari Fujioka, Prabha Nepal, Atsushi Tsuzuki, Ozora Aoki, Sarad Paudel, Hitoshi Sasajima, Yusuke Ohba
    • Journal Title

      Cell Structure and Function

      Volume: 44 Issue: 2 Pages: 183-194

    • DOI

      10.1247/csf.19028

    • NAID

      130007775556

    • ISSN
      0386-7196, 1347-3700
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Analysis of non-apoptotic cell death mediated by dopamine catabolism under inhibition of mitochondrial respiration2018

    • Author(s)
      Sasajima H, Fujioka Y, Sato A, Nepal P, Kashiwagi S, Tsuzuki A, Aoki O, Fujioka M, Yoshida A, Paudel S, Nanbo A, Ohba Y
    • Organizer
      第41回 日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] ドパミン代謝とミトコンドリア機能障害の合成神経毒性に対するハーブ由来抗酸化成分カルノシン酸、ロズマリン酸の効果.2017

    • Author(s)
      笹島仁, 野口智弘, 宮園貞治, 柏柳誠
    • Organizer
      日本味と匂学会第51回大会
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2024-01-30  

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