Alterations of proteolytic processing of synaptic adhesion molecules in Alzheimer disease

• Project/Area Number: 24659028
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: TOMITA Taisuke 東京大学, 大学院・薬学系研究科, 准教授 (30292957)
• Project Period (FY): 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2012: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 神経細胞 / シナプス / 接着分子

Research Abstract

In brain, each single neuron is connected to other neurons via synapses. Synapses can change their strength in response to neuronal activity, and synaptic adhesion molecules are implicated in the synapse plasticity. However, the metabolism of the synaptic adhesion molecules remains unknown. In the research, we found that neuroligin 1, which is associated with autism spectrum disorder, is sequentially processed by two proteases. This processing is modulated by synaptic activity and negatively regulates synapse formation in vivo.

Research Products

• [Journal Article] Structural biology of presenilins and signal peptide peptidases (2013)
  • Author(s): To mita T, Iwatsubo T
  • Journal Title: J Biol Chem Volume: 288(21) Issue: 21 Pages: 14673-14680
  • DOI: 10.1074/jbc.r113.463281
• [Journal Article] FTY720/Fingolimod, a sphingosine analogue, reduces amyloid-〓 production in neurons (2013)
  • Author(s): Takasugi N, Sasaki T, Ebinuma I, Osawa S, Isshiki H, Takeo K, Tomita T, Iwatsubo T
  • Journal Title: PloS ONE Volume: 8(5) Issue: 5 Pages: e64050-e64050
  • DOI: 10.1371/journal.pone.0064050
• [Journal Article] Effect of Helical Conformation and Side-Chain Structure on y-Secretase Inhibition by β-Peptide Foldamers : Insight into Substrate Recognition (2013)
  • Author(s): Yuki Imamura, Naoki Umezawa, Satoko Osawa, Naoaki Shimada, Takuya Higo, Satoshi Yokoshima, Tohru Fukuyama, Takeshi Iwatsubo, Nobuki Kato, Taisuke Tomita, Tsunehiko Higuchi
  • Journal Title: J. Med. Chem. Volume: 56 Issue: 4 Pages: 1443-1454
  • DOI: 10.1021/jm301306c
  • Peer Reviewed
• [Journal Article] Inhibition of g-secretase activity by a monoclonal antibody against the extracellular hydrophilic loop of presenilin 1 (2013)
  • Author(s): Shizuka Takagi-Niidome
  • Journal Title: Biochemistry Volume: 52 Issue: 1 Pages: 61-69
  • DOI: 10.1021/bi301252r
  • Peer Reviewed
• [Journal Article] Effect of Helical Conformation and Side Chain Structure on gamma-Secretase Inhibition by beta-Peptide Foldamers: Insight into Substrate Recognition. (2013)
  • Author(s): Imamura Y
  • Journal Title: J Med Chem Volume: in press
  • Peer Reviewed
• [Journal Article] FTY720/Fingolimod, a sphingosine analogue, reduces amyloid-beta production in neurons. (2013)
  • Author(s): Takasugi N
  • Journal Title: PLoS ONE Volume: in press
  • Peer Reviewed
• [Journal Article] Structural biology of presenilins and signal peptide peptidases. (2013)
  • Author(s): Tomita T
  • Journal Title: J Biol Chem Volume: in press
  • Peer Reviewed
• [Journal Article] Activity-dependent proteolytic cleavage of neuroligin-1 (2012)
  • Author(s): Suzuki K, Hayashi Y, Nakahara S, Kumazaki H, Prox J, Horiuchi K, Zeng M, Tanimura S, Nishiyama Y, Osawa S, Sehara-Fujisawa A, Saftig P, Yokoshima S, Fukuyama T, Matsuki N, Koyama R, Tomita T, Iwatsubo T.
  • Journal Title: Neuron Volume: 76(2) Issue: 2 Pages: 410-422
  • DOI: 10.1016/j.neuron.2012.10.003
  • Peer Reviewed
• [Journal Article] Contribution of〓-secretase cofactors to the formation of catalytic pore of presenilin 1 (2012)
  • Author(s): Takeo K, Watanabe N, Tomita T, Iwatsubo T
  • Journal Title: J Biol Chem Volume: 287(31) Issue: 31 Pages: 25834-25843
  • DOI: 10.1074/jbc.m111.336347
  • Peer Reviewed
• [Presentation] セクレターゼ活性の制御とシナプス機能の分子連関 (2013)
  • Author(s): 富田泰輔
  • Organizer: 日本薬学会133年会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-28
• [Presentation] Activity-dependent proteolytic cleavage of Neuroligin 1 (2012)
  • Author(s): Taisuke Tomita, Kunimichi Suzuki, Takeshi Iwatsubo
  • Organizer: The 35th Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 2012-12-13
• [Presentation] gamma-secretase活性中心サブユニットPresenilin1の第4膜貫通領域の構造解析 (2012)
  • Author(s): 富永綾、富田泰輔、岩坪威
  • Organizer: 第31回日本認知症学会学術集会
  • Place of Presentation: つくば
  • Year and Date: 2012-10-26
• [Presentation] The alpha-helical structure of the hydrophilic loop 1 of presenilin 1 contributes to the formation of the substrate binding site (2012)
  • Author(s): Taisuke Tomita
  • Organizer: Neuroscience 2012
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2012-10-13
• [Presentation] The alpha-helical structure of the hydrophilic loop1 of presenilin 1 contributes to the formation of the substrate binding site. (2012)
  • Author(s): Tomita T
  • Organizer: Neuroscience 2012
  • Place of Presentation: New Orleans, USA
• [Presentation] Activity-dependent proteolytic cleavage of Neuroligin 1. (2012)
  • Author(s): Tomita T
  • Organizer: The 35th Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: Fukuoka
  • Invited
• [Book] 自閉症に関連する タンパク質 Neuroligin の神経活動に依 存的な代謝はニューロンのシナプス形 成を制御している ライフサイエンス 新着論文レビュー (2012)
  • Author(s): 富田泰輔、鈴木邦道
• [Book] シナプス接着分子neuroligin-1の神経活動依存的なタンパク質切断 (2012)
  • Author(s): 鈴木邦道、富田泰輔、岩坪威
  • Publisher: 実験医学vol31
• [Remarks]
  • URL: http://www.f.u-tokyo.ac.jp/~neuropsc/entranceja2.html
• [Remarks] 研究室ホームページ
  • URL: http://www.f.u-tokyo.ac.jp/~neuropsc/