Dock family proteins in neurodegeneration

2013 Fiscal Year Final Research Report

• Project/Area Number: 23300138
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: NAMEKATA Kazuhiko 公益財団法人東京都医学総合研究所, 運動・感覚システム研究分野, 副参事研究員 (70392355)
• Co-Investigator(Renkei-kenkyūsha): GUO Xiaoli 公益財団法人東京都医学総合研究所, 運動・感覚システム研究分野, 主任研究員 (50443114) ; KIMURA Atsuko 公益財団法人東京都医学総合研究所, 運動・感覚システム研究分野, 主任研究員 (60569143) ; WATANABE Hayaki 公益財団法人東京都医学総合研究所, 運動・感覚システム研究分野, 研究員 (70595587)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: Dock3 / 緑内障 / 神経保護 / 神経変性疾患

Research Abstract

Dock3 is a guanine nucleotide exchange factors for the small GTPase Rac1. We found that Dock3 directly binds to NR2B, an N-methyl-D-aspartate (NMDA) receptor subunit. In transgenic mice overexpressing Dock3 (Dock3 Tg), NR2B expression in the retina was significantly decreased and NMDA-induced retinal degeneration was ameliorated. In addition, overexpression of Dock3 protected retinal ganglion cells (RGCs) from oxidative stress. We previously reported that RGC degeneration due to glutamate neurotoxicity and oxidative stress is observed in GLAST-deficient (KO) mice. In GLAST KO mice, the NR2B phosphorylation rate in the retina was significantly higher compared with Dock3 Tg:GLAST KO mice. Consistently, glaucomatous retinal degeneration was significantly improved in GLAST KO:Dock3 Tg mice compared with GLAST KO mice. These results suggest that Dock3 overexpression prevents glaucomatous retinal degeneration by suppressing both NR2B-mediated glutamate neurotoxicity and oxidative stress.

Research Products

• [Journal Article] Dock3 attenuates neural cell death due to NMDA neurotoxicity and oxidative stress in a mouse model of normal tension glaucoma (2013)
  • Author(s): Namekata K, Kimura A, Kawamura K, Guo X, Harada C, Tanaka K, Harada, T
  • Journal Title: Cell Death and Differentiation Volume: 20 Pages: 1250-1256
  • Peer Reviewed
• [Journal Article] Dock3 interaction with a glutamate-receptor NR2D subunit protects neurons from excitotoxicity (2013)
  • Author(s): Bai N, Hayashi H, Aida T, Namekata K, Harada T, Mishina M, Tanaka K
  • Journal Title: Molecular Brain 4 Volume: 6 Pages: 22
  • Peer Reviewed
• [Journal Article] Inhibition of ASK1-p38 pathway prevents neural cell death following optic nerve injury (2013)
  • Author(s): Katome, T., Namekata, K., Guo, X., Semba, K., Kittaka, D., Kawamura, K., Kimura, A., Harada, C., Ichijo, H., Mitamura, Y. and Harada, T
  • Journal Title: Cell Death and Differentiation Volume: 20 Pages: 270-280
  • Peer Reviewed
• [Journal Article] Expression of promyelocytic leukemia protein and vascular endothelial growth factor in aqueous humor and vitreous fluid in patients with proliferative diabetic retinopathy (2012)
  • Author(s): Katome T, Namekata K, Naito T, Semba K, Guo X, Harada C, Harada T, Mitamura Y
  • Journal Title: Diabetes Research and Clinical Practice Volume: 98(2) Pages: e9-e11
  • Peer Reviewed
• [Journal Article] Dock3 regulates BDNF-TrkB signaling for neurite outgrowth by forming a ternary complex with Elmo and RhoG (2012)
  • Author(s): Namekata K, Watanabe H, Guo X, Kittaka D, Kawamura K, Kimura A, Harada C, Harada T
  • Journal Title: Genes Cells Volume: 17(8) Pages: 688-97
  • Peer Reviewed
• [Journal Article] Dock3 stimulates axonal outgrowth via GSK-3β-mediated microtubule assembly (2012)
  • Author(s): Namekata K, Harada C, Guo X, Kimura A, Kittaka D, Watanabe H, and Harada T
  • Journal Title: Journal of Neuroscience Volume: 32 (1) Pages: 264-274
  • Peer Reviewed
• [Journal Article] Glia- and neuron-specific functions of TrkB signaling during retinal degeneration and regeneration (2011)
  • Author(s): Harada C, Guo X, Namekata K, Kimura A, Nakamura K, Tanaka K, Parada LF, Harada T
  • Journal Title: Nature Communications Volume: 2 Pages: 189
  • Peer Reviewed
• [Journal Article] Spermidine alleviates severity of murine experimental autoimmune encephalomyelitis (2011)
  • Author(s): Guo X, Harada C, Namekata K, Kimura A., Mitamura Y., Yoshida H., Matsumuto Y., Harada T
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 52(5) Pages: 2696-2703
  • Peer Reviewed
• [Presentation] Dock8 is a therapeutic target for CNS inflammation (2013)
  • Author(s): Kazuhiko Namekata, Chikako Harada, Xiaoli Guo, Takayuki Harada
  • Organizer: 43rd Annual Meeting of the Society for Neuroscience
  • Place of Presentation: San Diego
  • Year and Date: 2013-11-10
• [Presentation] Roles of ASK1 in neuroprotection and axonal regeneration after optic nerve injury (2013)
  • Author(s): Daiji Kittaka, Kazuhiko Namekata, Takuji Kurimoto, Xiaoli Guo, Chikako Harada, Takayuki Harada
  • Organizer: 43rd Annual Meeting of the Society for Neuroscience
  • Place of Presentation: San Diego
  • Year and Date: 2013-11-10
• [Presentation] Interaction between renin-angiotensin and innate immune systems inautoimmune neuroinflammation (2013)
  • Author(s): Xiaoli Guo, Kazuhiko Namekata, Chikako Harada, Takayuki Harada
  • Organizer: 43rd Annual Meeting of the Society for Neuroscience
  • Place of Presentation: San Diego
  • Year and Date: 2013-11-10
• [Presentation] Dock3 を活用した網膜・視神経再生研究シンポジウム「網膜再生医療の現状と今後」 (2013)
  • Author(s): 行方和彦
  • Organizer: 第117回日本眼科学会総会
  • Place of Presentation: 東京
  • Year and Date: 2013-04-04
  • Invited
• [Presentation] ASK1-p38 経路の阻害は視神経外傷による神経細胞死を抑制する (2013)
  • Author(s): 香留崇, 仙波賢太郎, 行方和彦, 原田高幸, 三田村佳典
  • Organizer: 第117回日本眼科学会総会
  • Place of Presentation: 東京
  • Year and Date: 2013-04-04
• [Presentation] The role of Dock3 in axon regeneration following optic nerve injury (2012)
  • Author(s): Namekata K, Harada C, Guo X, Kimura A, Harada T
  • Organizer: Poster session : Retinal cell biology, XX International Congress of Eye Research (ISER 2012)
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2012-07-24
• [Presentation] ASK1 inhibition ameliorates optic neuritis by modulating glial innate immunity. Oral session : Macrophages and micro glial regulation of ocular inflammation (2012)
  • Author(s): Guo X, Harada C, Namekata K, Kimura A, Harada T
  • Organizer: XX International Congress of Eye Research (ISER2012)
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2012-07-23
• [Presentation] 緑内障のモデルマウス網膜におけるタウのリン酸化 (2012)
  • Author(s): 行方和彦
  • Organizer: タウ研究ミーティング
  • Place of Presentation: 同志社大学
  • Year and Date: 2012-06-10
  • Invited
• [Presentation] Dock3によるマウス視神経軸索再生効果の検討 (2012)
  • Author(s): 原田高幸, 行方和彦, 原田知加子
  • Organizer: 第116回日本眼科学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-04-06
• [Presentation] Glia- and neuron-specific functions of TrkB signaling during retinal degeneration and regeneration (2011)
  • Author(s): Harada T, Guo X, Namekata K, Luis F. Parada, Harada C
  • Organizer: 8th World Congress of Neuroscience, International Brain Research Organization (IBRO)
  • Place of Presentation: Florence, Italy
  • Year and Date: 2011-07-18
• [Presentation] ASK1 inhibition ameliorates optic neuritis by modulating glial innate immunity (2011)
  • Author(s): Guo X., Harada C., Namekata K., Kimura A., Ichijo H. & Harada T
  • Organizer: 26th Asia Pacific Academy of Ophthalmology (APAO) Congress
  • Place of Presentation: Sydney
  • Year and Date: 2011-03-22
• [Presentation] ASK1 deficiency attenuates neural cell death in a mouse model of normal tension glaucoma (2011)
  • Author(s): Harada T., Namekata K., Guo X., Tanaka K., Ichijo H. & Harada C
  • Organizer: 26th Asia Pacific Academy of Ophthalmology (APAO) Congress
  • Place of Presentation: Sydney
  • Year and Date: 2011-03-22
• [Presentation] Optic Nerve Regeneration is Enhanced in Dock3 Overexpressing Transgenic Mice (2011)
  • Author(s): Namekata K., Harada C., Guo X. & Harada T
  • Organizer: 26th Asia Pacific Academy of Ophthalmology (APAO) Congress
  • Place of Presentation: Sydney
  • Year and Date: 2011-03-22
• [Book] Dock3 は正常眼圧緑内障モデルマウスにおいてグルタミン酸毒性と酸化ストレスによる神経細胞死を抑制する (2013)
  • Author(s): 行方和彦, 原田高幸
  • Publisher: BioMed サーカス.com 研究論文ハイライト
  • URL: http://biomedcircus.com/paper_03_20.html
• [Book] ASK1-p38 経路の阻害は視神経外傷後の神経細胞死を抑制する 日本眼科学会雑誌 (2013)
  • Author(s): 香留 崇, 行方和彦, 郭 暁麗, 仙波賢太郎, 橘高大二, 川村和人, 木村敦子, 原田知加子, 一條秀憲, 三田村佳典, 原田高幸
  • Total Pages: 117:161
• [Book] Dock3 はグリコーゲン合成酵素キナーゼ-3β (GSK-3β)による微小管重合を介して視神経軸索の再生を促進する (2012)
  • Author(s): 行方和彦, 原田高幸
  • Publisher: BioMed サーカス.com 研究論文ハイライト
  • URL: http://biomedcircus.com/paper_03_01.html
• [Book] 神経軸索の再生におけるDock3の機能,日本生化学会誌 (2012)
  • Author(s): 行方和彦, 原田幸
  • Total Pages: 84(5), 368
• [Book] Dock3 はグリコーゲン合成酵素キナーゼ-3β (GSK-3β)による微小管重合を介して軸索伸長を促進する 日本眼科学会会誌 (2012)
  • Author(s): 行方和彦, 原田知加子, 郭 暁麗, 木村敦子, 橘高大二, 渡邉快記, 原田高幸
  • Total Pages: 116(5), 527
• [Book] Spermidine 投与による実験的自己免疫性脳脊髄炎の軽症化 日本眼科学会会誌 (2011)
  • Author(s): 郭 暁麗, 原田知加子, 行方和彦, 木村敦子, 三田村佳典, 吉田 寛, 松本 陽, 原田高幸
  • Total Pages: 115(8), 729
• [Book] 網膜の変性と再生過程におけるグリアおよび神経特異的なTrkB シグナルの機能解析 日本眼科学会会誌 (2011)
  • Author(s): 原田知加子, 郭 暁麗, 行方和彦, 木村敦子, 中村和昭, 田中光一, Luis F. Parada, 原田高幸
  • Total Pages: 115(7), 637
• [Book] TLR-ASK1-p38経路による神経炎症と脱髄症状の制御 日本眼科学会会誌 (2011)
  • Author(s): 郭 暁麗, 原田知加子, 行方和彦, 松沢厚, Monsterrat Camps, Hong Ji, Dominique Swinnen, Catherine Jorand-Lebrun, Mathilde Muzerelle, Pierre-Alain Vitte, Thomas Rückle, 木村敦子, 神山邦子, 松本 陽, 一條秀憲, 原田高幸
  • Total Pages: 115(5), 485
• [Remarks]
  • URL: http://www.igakuken.or.jp
• [Patent(Industrial Property Rights)] Dock8を含む神経炎症又は脱髄疾患の予防又は治療用医薬組成物 (2013)
  • Inventor(s): 原田高幸, 行方和彦, 郭 暁麗
  • Industrial Property Rights Holder: 公益財団法人東京都医学総合研究所
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2013-026753
  • Filing Date: 2013-02-18