Dock family proteins in demyelination and neuroinflammation

• Project/Area Number: 25640043
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• 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)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); 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: Dock3 / 脱髄疾患 / 神経変性 / Dock8 / Dockファミリー / 視神経炎症 / EAE

Outline of Final Research Achievements

Oligodendrocytes are the myelinating cells of axons in the central nervous system and these cells are damaged in demyelinating disorders including multiple sclerosis (MS) and optic neuritis. We examined if Dock3 can suppress demyelination in a cuprizone-induced demyelination model, an animal model of MS. We demonstrate that Dock3 overexpression protects myelin in the corpus callosum following cuprizone treatment. Furthermore, we show that cuprizone demyelinates optic nerves and the extent of demyelination is ameliorated in mice overexpressing Dock3. Cuprizone treatment impairs visual function, which was demonstrated by multifocal electroretinograms, an established non-invasive method, and Dock3 overexpression prevented this effect. In mice overexpressing Dock3, Erk activation is increased, suggesting this may at least partly explain the observed protective effects. Our findings suggest that Dock3 may be a therapeutic target for demyelinating disorders.

Research Products

• [Journal Article] Spermidine promotes retinal ganglion cell survival and optic nerve regeneration in adult mice following optic nerve injury. (2015)
  • Author(s): Noro, T., Namekata, K., Kimura, A., Guo, X., Azuchi, Y., Harada, C., Nakano, T., Tsuneoka, H. and Harada, T.
  • Journal Title: Cell Death and Disease Volume: 6 Issue: 4 Pages: e1720-e1720
  • DOI: 10.1038/cddis.2015.93
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Valproic acid prevents NMDA-induced retinal ganglion cell death via stimulation of neuronal TrkB receptor signaling (2015)
  • Author(s): Kimura, A., Namekata, K., Guo, X., Noro, T., Harada, C. and Harada, T.
  • Journal Title: American Journal of Pathology Volume: 185 Issue: 3 Pages: 756-764
  • DOI: 10.1016/j.ajpath.2014.11.005
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Brimonidine suppresses loss of retinal neurons and visual function in a murine model of optic neuritis (2015)
  • Author(s): Guo, X., Namekata, K., Kimura, A., Noro, T., Azuchi, Y., Semba, K., Harada, C., Yoshida, H., Mitamura, Y. and Harada, T.
  • Journal Title: Neuroscience Letters Volume: 592 Pages: 27-31
  • DOI: 10.1016/j.neulet.2015.02.059
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Valproic acid prevents retinal degeneration in a murine model of normal tension glaucoma (2015)
  • Author(s): Kimura, A., Guo, X., Noro, T., Harada, C., Tanaka, K., Namekata, K. and Harada, T
  • Journal Title: Neuroscience Letters Volume: 588 Pages: 108-113
  • DOI: 10.1016/j.neulet.2014.12.054
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Expression of intraocular peroxisome proliferator-activated receptor gamma in patients with proliferative diabetic retinopathy. (2015)
  • Author(s): Katome T, Namekata K, Mitamura Y, Semba K, Egawa M, Naito T, Harada C, Harada T
  • Journal Title: J Diabetes Complications Volume: 29 Issue: 2 Pages: 275-281
  • DOI: 10.1016/j.jdiacomp.2014.10.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Arundic acid attenuates retinal ganglion cell death by increasing glutamate/aspartate transporter expression in a model of normal tension glaucoma. (2015)
  • Author(s): Yanagisawa, M., Aida, T., Takeda, T., Namekata, K., Harada, T., Shinagawa, R. and *Tanaka. K.
  • Journal Title: Cell Death and Disease Volume: 6 Issue: 3 Pages: e1693-e1693
  • DOI: 10.1038/cddis.2015.45
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Renin-angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma (2015)
  • Author(s): Semba, K., Namekata, K., Guo, X., Harada, C., Harada, T. and Mitamura, Y
  • Journal Title: Cell Death and Disease Volume: 5 Issue: 7 Pages: e1333-e1333
  • DOI: 10.1038/cddis.2014.296
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dock3 protects myelin in the cuprizone model for demyelination. (2014)
  • Author(s): Namekata K, Kimura A, Harada C, Yoshida H, Matsumoto Y, Harada T.
  • Journal Title: Cell Death Dis. Volume: 5 Issue: 8 Pages: e1395-e1395
  • DOI: 10.1038/cddis.2014.357
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Brimonidine prevents neurodegeneration in a mouse model of normal tension glaucoma. (2014)
  • Author(s): Semba K, Namekata K, Kimura A, Harada C, Mitamura Y, Harada T
  • Journal Title: Cell Death Dis Volume: 5 Issue: 7 Pages: e1341-e1341
  • DOI: 10.1038/cddis.2014.306
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dock3 overexpression and p38 MAPK inhibition synergistically stimulate neuroprotection and axon regeneration after optic nerve injury. (2014)
  • Author(s): Semba K, Namekata K, Kimura A, Harada C, Katome T, Yoshida H, Mitamura Y, Harada, T
  • Journal Title: Neurosci Lett Volume: 581 Pages: 89-93
  • DOI: 10.1016/j.neulet.2014.08.034
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Dock GEFs and their therapeutic potential: neuroprotection and axon regeneration. (2014)
  • Author(s): Namekata K, Kimura A, Kawamura K, Harada C, Harada T.
  • Journal Title: Prog Retin Eye Res. Volume: 43 Pages: 1-16
  • DOI: 10.1016/j.preteyeres.2014.06.005
  • Peer Reviewed / Acknowledgement Compliant
• [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 Issue: 9 Pages: 1250-1256
  • DOI: 10.1038/cdd.2013.91
  • Peer Reviewed
• [Journal Article] Dock3 interaction with a glutamate-receptor NR2D subunit protects neurons from excitotoxicity (2013)
  • Author(s): Ning Bai, Hideki Hayashi, Tomomi Aida, Kazuhiko Namekata, Takayuki Harada, Masayoshi Mishina and Kohichi Tanaka
  • Journal Title: Molecular Brain Volume: 6 Issue: 1 Pages: 22-22
  • DOI: 10.1186/1756-6606-6-22
  • 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 Differ. Volume: 20 Issue: 2 Pages: 270-280
  • DOI: 10.1038/cdd.2012.122
  • Peer Reviewed
• [Presentation] permidine stimulates neuroprotection and optic nerve regeneration following optic nerve injury. (2015)
  • Author(s): Takahiko Noro, Kazuhiko Namekata, Xiaoli Guo, Atsuko Kimura, Yuriko Azuchi, Tadashi Nakano, Hiroshi Tsuneoka, Takayuki Harada.
  • Organizer: Asia-ARVO
  • Place of Presentation: Pacifico Yokohama, Yokohama
  • Year and Date: 2015-02-18
• [Presentation] Valproic acid protects retinal neurons from NMDA-induced neurotoxicity via stimulation of neuronal TrkB receptors. (2015)
  • Author(s): Atsuko Kimura, Kazuhiko Namekata, Xiaoli Guo, Takahiko Noro, Chikako Harada, Takayuki Harada.
  • Organizer: Asia-ARVO
  • Place of Presentation: Pacifico Yokohama, Yokohama
  • Year and Date: 2015-02-18
• [Presentation] 神経変性疾患における神経保護・軸索再生の研究. (2015)
  • Author(s): 行方和彦
  • Organizer: 第１７回東邦大学理学部生物分子科学賞記念講演
  • Place of Presentation: 東邦大学 千葉県習志野市
  • Year and Date: 2015-01-06
  • Invited
• [Presentation] Dock8/10 regulate severity of inflammatory demyelination disorder. (2014)
  • Author(s): Kazuhiko Namekata, Xiaoli Guo, Atsuko Kimura, Chikako Harada, Takayuki Harada.
  • Organizer: The ARVO (The Association for Research in Vision and Ophthalmology)
  • Place of Presentation: U.S.A. Orlando
  • Year and Date: 2014-05-08
• [Presentation] Combined inhibition of angiotensin II type 1 receptor and ASK1 significantly attenuates autoimmune optic neuritis. (2014)
  • Author(s): Xiaoli Guo, Kazuhiko Namekata, Chikako Harada, Takayuki Harada.
  • Organizer: The ARVO (The Association for Research in Vision and Ophthalmology)
  • Place of Presentation: U.S.A. Orlando
  • Year and Date: 2014-05-08
• [Presentation] Dock3 protects retinal neurons in a mouse model of normal tension glaucoma. (2014)
  • Author(s): Kazuhiko Namekata, Xiaoli Guo, Chikako Harada, Takayuki Harada.
  • Organizer: The 2014 World Ophthalmology Congress
  • Place of Presentation: 東京国際ファーラム 東京
  • Year and Date: 2014-04-03
• [Presentation] Inhibition of Angiotensin II Ameliorates Autoimmune Optic Neuritis by Suppressing Innate Immune Responses. (2014)
  • Author(s): Xiaoli Guo, Kazuhiko Namekata, Chikako Harada, Takayuki Harada.
  • Organizer: The 2014 World Ophthalmology Congress
  • Place of Presentation: 東京国際ファーラム 東京
  • Year and Date: 2014-04-03
• [Presentation] Dock8 is a therapeutic target for CNS inflammation.
  • Author(s): Kazuhiko Namekata, Chikako Harada, Xiaoli Guo, Takayuki Harada.
  • Organizer: 43rd Annual Meeting of the Society for Neuroscience
  • Place of Presentation: San Diego, USA
• [Presentation] Interaction between renin-angiotensin and innate immune systems in autoimmune neuroinflammation.
  • Author(s): Xiaoli Guo, Kazuaki Nakamura, Chikako Harada, Kuniko Kohyama, Heather A. Behanna, D. Martin Watterson, Yoh Matsumoto, Takayuki Harada.
  • Organizer: 43rd Annual Meeting of the Society for Neuroscience
  • Place of Presentation: San Diego, USA
• [Presentation] Roles of ASK1 in neuroprotection and axonal regeneration after optic nerve injury.
  • 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, USA
• [Presentation] Dock3を活用した網膜・視神経再生研究
  • Author(s): 行方和彦.
  • Organizer: 第117回日本眼科学会総会
  • Place of Presentation: 東京
  • 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
  • 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
• [Book] Optic nerve regeneration. Neuroprotection and Neuroregeneration for Retinal Diseases. (2014)
  • Author(s): Kazuhiko Namekata, Takayuki Harada (Toru Nakazawa, Yasushi Kitaoka, Takayuki Harada, eds)
  • Total Pages: 356
  • Publisher: Springer Japan
• [Remarks] 公益財団法人東京都医学総合研究所
  • URL: http://www.igakuken.or.jp