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A novel therapeutic target for neurological disoders by inhibition of GAPDH aggregation

Research Project

Project/Area Number 25450428
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Veterinary medical science
Research InstitutionOsaka Prefecture University

Principal Investigator

Nakajima Hidemitsu  大阪府立大学, 生命環境科学研究科(系), 准教授 (30405360)

Co-Investigator(Kenkyū-buntansha) KUWAMURA Mitsuru  大阪府立大学, 生命環境科学研究科・獣医学専攻, 准教授 (20244668)
Co-Investigator(Renkei-kenkyūsha) YUBA Eiji  大阪府立大学, 工学研究科, 助教 (80582296)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords脳神経疾患 / GAPDH / アルツハイマー病 / 脳卒中 / 酸化ストレス / 創薬 / ペプチドミミック / 凝集阻害剤 / アミロイド / 阻害剤 / ミトコンドリア / PARP / 凝集 / 核移行 / 治療薬
Outline of Final Research Achievements

Glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a homotetrameric protein that also mediates cell death under oxidative stresses. We previously reported that intermolecular disulfide-bonding GAPDH aggregates through oxidation of the active site cysteine (Cys-152) participate in oxidative stress-induced cell death. We also revealed that the active site cysteine-null GAPDH (C152A-GAPDH) rescues oxidative stress-induced neuronal cell death in a dominant negative manner via the formation of these hybrid tetramer both in vitro and in vivo. Here we report that this dominant negative C152A-GAPDH mutant against endogenous GAPDH aggregation in response to oxidative stress ameliorated neuronal cell death in neurological models using a specific inhibitor of GAPDH aggregation (GAI-X) exerted decrease of neurological dysfunctions. These findings provide a therapeutic avenue of new drug target for the brain damages such as Stroke and Alzheimer disease.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (14 results)

All 2016 2015 2013 Other

All Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 3 results,  Acknowledgement Compliant: 2 results) Presentation (5 results) (of which Int'l Joint Research: 2 results) Remarks (3 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Active site cysteine-null glyceraldehyde-3-phosphate dehydrogenase (GAPDH) rescues nitric oxide-induced cell death.2016

    • Author(s)
      Kubo T., Nakajima H., Nakatsuji M., Itakura M., Kaneshige A., Azuma Y. T., Inui T., and Takeuchi T.
    • Journal Title

      Nitric Oxide

      Volume: 53 Pages: 13-21

    • DOI

      10.1016/j.niox.2015.12.005

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glyceraldehyde-3-phosphate dehydrogenase aggregation inhibitor peptide: A potential therapeutic strategy against oxidative stress-induced cell death.2015

    • Author(s)
      Itakura M, Nakajima H, Semi Y, Higashida S, Azuma YT, Takeuchi T.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 2015 Issue: 2 Pages: 373-376

    • DOI

      10.1016/j.bbrc.2015.09.150

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Glyceraldehyde-3-phosphate Dehydrogenase Aggregates Accelerate Amyloid-β Amyloidogenesis in Alzheimer Disease.2015

    • Author(s)
      Itakura, M., Nakajima, H., Kubo, T., Semi, Y., Kume, S., Higashida, S., Kaneshige, A., Kuwamura, M., Harada, N., Kita, A., Azuma, Y. T., Yamaji, R., Inui, T., Takeuchi, T.
    • Journal Title

      J. Biol. Chem.

      Volume: 290 Issue: 43 Pages: 26072-26087

    • DOI

      10.1074/jbc.m115.669291

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of Apoptosis Signal-regulating Kinase 1 (ASK1) as an activator of the GAPDH-Siah1 Stress-Signaling Cascade.2015

    • Author(s)
      Tristan C.A., Ramos A., Shahani N., Emiliani F.E., Nakajima H., Noeh C.C., Kato Y., Takeuchi T., Noguchi T., Kadowaki H., Sedlak T.W., Ishizuka K., Ichijo H., Sawa, A.
    • Journal Title

      The Journal of Biological Chemistry

      Volume: 290 Issue: 1 Pages: 56-64

    • DOI

      10.1074/jbc.m114.596205

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nuclear-translocated glyceraldehyde-3-phosphate dehydrogenase promotes poly(ADP-ribose) polymerase-1 activation during oxidative/nitrosative stress in stroke.2015

    • Author(s)
      Nakajima H, Kubo T, Ihara H, Hikida T, Danjo T, Nakatsuji M, Shahani N, Itakura M, Ono Y, Azuma Y, Inui T, Kamiya A, Sawa A, Takeuchi T
    • Journal Title

      J. Biol. Chem.

      Volume: VOL. 290 Issue: 23 Pages: 14493-14503

    • DOI

      10.1074/jbc.m114.635607

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Glycelaldehyde-3-phosphate dehydrogenase (GAPDH) aggregates contribute to the pathogenesis of Alzheimer’s disease.2016

    • Author(s)
      板倉正典、中嶋秀満、東田周作、瀬見優子、久保岳也、東 泰孝、竹内正吉
    • Organizer
      第89回日本薬理学会年会
    • Place of Presentation
      神奈川県横浜市・パシフィコ横浜会議センター
    • Year and Date
      2016-03-10
    • Related Report
      2015 Annual Research Report
  • [Presentation] Glyceraldehyde-3-phosphate dehydrogenase aggregation inhibitor: Exploring a drug targeting for Alzheimer’s disease.2015

    • Author(s)
      Kita A, Kubo T, Semi Y, Higashida S, Kaneshige A, Itakura M, Azuma YT, Takeuchi T, Nakajima H.
    • Organizer
      45th annual meeting of the Society for Neuroscience
    • Place of Presentation
      米国イリノイ州シカゴ・McCormick Place
    • Year and Date
      2015-10-19
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Glyceraldehyde-3-phosphate dehydrogenase regulates c-jun N-terminal kinase activation under oxidative stress conditions.2015

    • Author(s)
      Sato K, Itakura M, Azuma YT, Takeuchi T, Nakajima H.
    • Organizer
      45th annual meeting of the Society for Neuroscience
    • Place of Presentation
      米国イリノイ州シカゴ・McCormick Place
    • Year and Date
      2015-10-18
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] アルツハイマー病の病態形成にGAPDH凝集体が関与する.2015

    • Author(s)
      板倉正典、中嶋秀満、東田周作、瀬見優子、久保岳也、東 泰孝、竹内正吉
    • Organizer
      第158回日本獣医学会学術集会
    • Place of Presentation
      青森県十和田市北里大学
    • Year and Date
      2015-09-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] GAPDH凝集阻害による新規アルツハイマー病治療薬の創製2013

    • Author(s)
      8.東田周作、久保岳也、板倉正典、中嶋秀満、東 泰孝、竹内正吉
    • Organizer
      第123回日本薬理学会近畿部会
    • Place of Presentation
      名古屋
    • Related Report
      2013 Research-status Report
  • [Remarks] Veterinary Pharmacology

    • URL

      http://www.vet.osakafu-u.ac.jp/pham/

    • Related Report
      2015 Annual Research Report
  • [Remarks] GEヘルスケア・ジャパン株式会社

    • URL

      http://www.gelifesciences.co.jp/technologies/dharmacon/pdf/3795_dharmacon_accell_sirna_voc.pdf#search='%E4%B8%AD%E5%B6%8B%E7%A7%80%E6%BA%80'

    • Related Report
      2015 Annual Research Report
  • [Remarks] 大阪府立大学 獣医学専攻 応用薬理学教室

    • URL

      http://www.vet.osakafu-u.ac.jp/pham/pham.html

    • Related Report
      2014 Research-status Report
  • [Patent(Industrial Property Rights)] GAPDH凝集阻害剤2015

    • Inventor(s)
      中嶋秀満
    • Industrial Property Rights Holder
      中嶋秀満
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2015-116140
    • Filing Date
      2015-06-08
    • Related Report
      2015 Annual Research Report

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Published: 2014-07-25   Modified: 2019-07-29  

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