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

• Project/Area Number: 25450428
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Veterinary medical science
• Research Institution: Osaka 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: ¥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.

Research Products

• [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
  • 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
  • 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
  • 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
  • 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
  • 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
• [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
  • 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
  • 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
• [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
• [Remarks] Veterinary Pharmacology
  • URL: http://www.vet.osakafu-u.ac.jp/pham/
• [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'
• [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
• [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