Functional analysis of alpha1,6-fucosyltransferase deficient mice and underlying molecular mechanism

• Project/Area Number: 24590087
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Tohoku Pharmaceutical University
• Principal Investigator: FUKUDA Tomohiko 東北薬科大学, 薬学部, 准教授 (40433510)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 糖転移酵素 / フコース / 膜タンパク質 / AMPA 受容体 / Fut8 / α1,6 フコース / 糖鎖 / 神経疾患ス / モデルマウ / 神経疾患 / モデルマウス

Outline of Final Research Achievements

We previously reported thatα1,6-fucosyltransferase (Fut8) knockout (Fut8-/-) mice showed a schizophrenia-like phenotype and a decrease in working memory. To understand the underlying molecular mechanism, we analyzed early-form long-term potentiation (E-LTP), which is closely related to learning and memory in the hippocampus. The scale of E-LTP induced by high frequency stimulation was significantly decreased in Fut8-/- mice. The expression levels of AMPARs in the postsynaptic density were enhanced in Fut8-/- mice, although there were no significant differences in the total expression levels, implicating that AMPARs without core fucosylation might exist in an active state. Taken together, loss of core fucosylation on AMPARs enhanced their heteromerization, which might increase sensitivity for postsynaptic depolarization, and persistently activate N-methyl-D-aspartate receptors as well as Ca2+ influx and CaMKII, and then impair LTP.

Research Products

• [Journal Article] Loss of α1,6-fucosyltransferase decreased hippocampal long-term potentiation: implication of core fucosylation in the regulation of AMPA receptor heteromerization and cellular signaling (2015)
  • Author(s): Wei Gu, Tomohiko Fukuda, Tomoya Isaji, Qinglei Hang, Ho-hsun Lee, Seiichiro Sakai, Jyoji Morise, Junya Mitoma, Hideyoshi Higashi, Naoyuki Taniguchi, Hiromu Yawo, Shogo Oka, Jianguo Gu
  • Journal Title: J Biol Chem. Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] α1,6-Fucosylation regulates neurite formation via the activin/phospho-Smad2 pathway in PC12 cells: the implicated dual effects of Fut8 for TGF-β/activin-mediated signaling. (2013)
  • Author(s): Gu, W., Fukuda, T., Isaji, T., Hashimoto, H., Wang., Y and Gu, J.
  • Journal Title: FASEB J Volume: 27 Issue: 10 Pages: 3947-3958
  • DOI: 10.1096/fj.12-225805
  • Peer Reviewed
• [Journal Article] Basement membrane assembly of the integrin α8β1 ligand nephronectin requires Fraser syndrome-associated proteins. (2012)
  • Author(s): Kiyozumi D, Takeichi M, Nakano I, Sato Y, Fukuda T, Sekiguchi K.
  • Journal Title: The Journal of Cell Biology Volume: 197 Issue: 5 Pages: 677-89
  • DOI: 10.1083/jcb.201203065
  • NAID: 120006626430
  • Peer Reviewed
• [Journal Article] Roles of N-acetylglucosaminyltransferase III in epithelial-to-mesenchymal transition induced by transforming growth factor β1 (TGF-β1) in epithelial cell lines. (2012)
  • Author(s): Xu Q, Isaji T, Lu Y, Gu W, Kondo M, Fukuda T, Du Y, Gu J.
  • Journal Title: Journal of Biological Chemistry Volume: 286 Issue: 20 Pages: 16563-74
  • DOI: 10.1074/jbc.m111.262154
  • Peer Reviewed
• [Journal Article] Potential roles of N-glycosylation in cell adhesion. (2012)
  • Author(s): Gu, J., et al
  • Journal Title: Glycoconj J Volume: 29 Issue: 8-9 Pages: 599-607
  • DOI: 10.1007/s10719-012-9386-1
  • Peer Reviewed
• [Presentation] Functional analysis of α1,6-fucosyltransferase deficient mice and underlying molecular mechanism (2014)
  • Author(s): 福田友彦、顧建国
  • Organizer: 第57回日本神経化学会
  • Place of Presentation: 奈良県文化会館・奈良県新公会堂(奈良県奈良市)
  • Year and Date: 2014-09-29 – 2014-10-01
• [Presentation] Impairment of hippocampal long-term potentiation and enhanced AMPA receptor complexes formation in alpha 1,6-fucosyltransferase-deficient mice (2014)
  • Author(s): Tomohiko Fukuda, Wei Gu, Tomoya Isaji, Seiichiro Sakai, Jyoji Morise, Hideyoshi Higashi, Naoyuki Taniguchi, Hiromu Yawo, Shogo Oka Jianguo Gu
  • Organizer: 9th International Symposium on Glycosyltransferases
  • Place of Presentation: Porto, Portugal
  • Year and Date: 2014-06-18 – 2014-06-21
• [Presentation] Mice lacking fucosyltransferase 8 exhibit abnormal behavioral abnormalities associated with a schizophrenia-like phenotype (2013)
  • Author(s): Fukuda T., Gu W., Isaji T., Taniguchi n. Gu J.
  • Organizer: Glycoconjugates-22(GLYCO-22)
  • Place of Presentation: Dalian
• [Presentation] α1,6 フコース転移酵素Fut8 欠損による海馬機能の変化 (2012)
  • Author(s): 福田友彦、顧威、橋本弘和、酒井 誠一郎、王玉琴、伊左治知弥、八尾寛、東秀好、顧建国
  • Organizer: 第31回日本糖質学会年
  • Place of Presentation: 鹿児島
• [Presentation] 脳神経における α1,6 フコースの機能解析 (2012)
  • Author(s): 福田 友彦, 顧 威, 伊左治 知弥, 王 玉琴, 顧 建国
  • Organizer: 第4回東北糖鎖研究会
  • Place of Presentation: 青森