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Development of fundamental therapy for dopamine-related disorders targetting novel protein complex V-1/CP

Research Project

Project/Area Number 16K08904
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Applied pharmacology
Research InstitutionTohoku University

Principal Investigator

KAWAHATA ICHIRO  東北大学, 薬学研究科, 助教 (30579743)

Research Collaborator Yamakuni Tohru  , 准教授
Kobayashi Kazuto  , 教授
Ichinose Hiroshi  , 教授
Hasegawa Kazuko  , 医師
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsV-1/CP complex / tyrosine hydroxylase / Nurr1 / dopamine / aging / Parkinson's disease / nicotine receptor / NMDA receptor / V-1/CP複合体 / 老化 / パーキンソン病 / アルツハイマー病 / ドパミン / チロシン水酸化酵素 / 血清応答因子 / アクチン重合 / カテコールアミン / 加齢 / ドーパ脱炭酸酵素 / NMDA受容体 / ドーパミン
Outline of Final Research Achievements

V-1/CP complex formation is essential to maintain dopaminergic function, and the complex promotes dopamine biosynthesis by some stimulation (KAKENHI23790594, 25860389). In this study, we approached the mechanism to activate V-1/CP complex and screened novel compounds targetting V-1/CP that facilitate the complex formation then verified their therapeutic effects. We revealed that the complex is activated by NMDA receptors and nicotinic acetylcholine receptors to potentiate dopaminergic function and neuroprotective abilities to enhance cell survival. Furthermore, we found the complex formation of V-1/CP was attenuated by aging and in the postmortem brain of human with Parkinson's disease (PD). We also successfully identified natural compounds targetting V-1/CP complex and revealed the compounds could activate the complex to recover dopaminergic function and cell survival in aged or PD model. Thus, the therapeutics targetting V-1/CP complex is useful for PD and anti-aging treatment.

Academic Significance and Societal Importance of the Research Achievements

日本では超高齢化が進み、高齢者で多発するパーキンソン病患者の数が増加している。パーキンソン病の対症療法薬はあるものの、これまで根本治療薬は開発されていない。私たちはV-1/CPという新しいタンパク質複合体に着目し、そのドパミン機能の強力な賦活化作用を明らかにしてきた。本研究では同複合体がNMDA受容体やニコチン受容体により活性化される新しい機序を明らかにし、同複合体を標的とした新たな化合物のスクリーニングに成功した。またパーキンソン病や加齢によって同複合体が減少し、新規化合物により回復可能であることを明らかにした。これらの成果から、同複合体を標的としたドパミン疾患治療薬の開発が期待できる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (13 results)

All 2018 2017 2016

All Journal Article (6 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 6 results,  Open Access: 3 results,  Acknowledgement Compliant: 1 results) Presentation (6 results) (of which Int'l Joint Research: 4 results,  Invited: 2 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Royal jelly coordinately enhances hippocampal neuronal expression of somatostatin and neprilysin genes conferring neuronal protection against toxic soluble amyloid-β oligomers implicated in Alzheimer’s disease pathogenesis2018

    • Author(s)
      Kawahata Ichiro、Xu Huinan、Takahashi Michiyo、Murata Kiyoshi、Han Wanying、Yamaguchi Yoshihisa、Fujii Akira、Yamaguchi Kikuji、Yamakuni Tohru
    • Journal Title

      Journal of Functional Foods

      Volume: 51 Pages: 28-38

    • DOI

      10.1016/j.jff.2018.10.006

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Imidacloprid, a neonicotinoid insecticide, facilitates tyrosine hydroxylase transcription and phenylethanolamine N -methyltransferase mRNA expression to enhance catecholamine synthesis and its nicotine-evoked elevation in PC12D cells2018

    • Author(s)
      Ichiro Kawahata and Tohru Yamakuni
    • Journal Title

      Toxicology

      Volume: 394 Pages: 84-92

    • DOI

      10.1016/j.tox.2017.12.004

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Fermented Citrus reticulata (ponkan) fruit squeezed draff that contains a large amount of 4′-demethylnobiletin prevents MK801-induced memory impairment2017

    • Author(s)
      Ichiro Kawahata, Tatsuya Suzuki, Evelyn Gutierrez Rico, Shuichi Kusano, Hiroshi Tamura, Yoshihiro Mimaki, Tohru Yamakuni
    • Journal Title

      Journal of Natural Medicines

      Volume: 71 Issue: 4 Pages: 617-631

    • DOI

      10.1007/s11418-017-1091-8

    • NAID

      40021337871

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Tyrosine hydroxylase gene expression is facilitated by alcohol followed by the degradation of the protein by ubiquitin proteasome system2017

    • Author(s)
      Ichiro Kawahata, Evelyn Gutierrez Rico, Xu Huinan, Shiori Ohtaku, Hasan Parvez, Yoshihisa Tomioka, Tohru Yamakuni
    • Journal Title

      Neuroendocrinology Letters

      Volume: 38 Pages: 43-49

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Tyrosine hydroxylase gene expression if facilitated by alcohol followed by the degradation of the protein by ubiquitin proteasome system2017

    • Author(s)
      Ichiro Kawahata, Gutierrez Rico Evelyn, Xu Huinan, Shiori Ohtaku, Yoshihisa Tomioka, Hasan Parvez, Tohru Yamakuni
    • Journal Title

      Neuroendocrinology Letters

      Volume: 38 Pages: 101-107

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Regulation of gene expression and degradation of tyrosine hydroxylase in Parkinson’s disease2016

    • Author(s)
      Ichiro Kawahata
    • Journal Title

      Arch Gen Intern Med

      Volume: 1 Pages: 1-3

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 新規タンパク質複合体による神経機能調節機構を標的としたパーキンソン病新薬開発へのアプローチ2018

    • Author(s)
      川畑 伊知郎
    • Organizer
      第69回日本薬理学会北部会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Novel protein complex for a potent therapeutic target in Alzheimer's disease and Parkinson's disease2018

    • Author(s)
      Ichiro Kawahata
    • Organizer
      International Conference of Asia Pacific Society for Biology and Medical Sciences 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] V-1/CP complex formation is required for genetic co-regulation of adult nigrostriatal dopaminergic homeostatis via the RHO/MAL/SRF pathway in vitro and in vivo2018

    • Author(s)
      Ichiro Kawahata, Yensin Lai, Junichi Morita, Shigeki Kato, Shiori Ohtaku, Yoshihisa Tomioka, Akiko Tabuchi, Masaaki Tsuda, Chiho Ichinose, Katsunori Kondo, Yasuhiko Izumi, Toshiaki Kume, Akinori Akaike, Kazumasa Ohashi, Kensaku Mizuno, Kazuko Hasegawa, Hiroshi Ichinose, Kazuto Kobayashi, Tohru Yamakuni
    • Organizer
      Neuroscience 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 国産柑橘種C.tachibana における抗認知症作用の分子薬理学的特性2017

    • Author(s)
      川畑 伊知郎
    • Organizer
      日本薬学会 第137年会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] V-1/CP complex formation is required for genetic co-regulation of adult nigrostriatal dopaminergic function via the RHO/MAL/SRF pathway in vitro and in vivo2017

    • Author(s)
      Ichiro Kawahata, Yensin Lai, Junichi Morita, Shigeki Kato, Shiori Ohtaku, Yoshihisa Tomioka, Akiko Tabuchi, Masaaki Tsuda, Chiho Ichinose, Katsunori Kondo, Yasuhiko Izumi, Toshiaki Kume, Akinori Akaike, Kazumasa Ohashi, Kensaku Mizuno, Kazuko Hasegawa, Hiroshi Ichinose, Kazuto Kobayashi, Tohru Yamakuni
    • Organizer
      XXIII World Congress of Neurology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Gene Analysis of Segawa disease at the neurological clinic for children2017

    • Author(s)
      Kyoko Hoshino, Kazue Kimura, Masaharu Hayashi, Yuri Nagao, Kei Hachimori, Yasuo Terao, Ichiro Kawahata, Haruo Shintaku, Hiroshi Ichinose
    • Organizer
      XXIII World Congress of Neurology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Patent(Industrial Property Rights)] アクチン細胞骨格安定化因子V-1のミトコンドリア恒常性維持活性とその賦活剤2017

    • Inventor(s)
      川畑伊知郎、山國徹
    • Industrial Property Rights Holder
      川畑伊知郎、山國徹
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Related Report
      2017 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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