Involvement of TDP-43 and FUS on translational and synaptic control and its relevance to ALS/FTLD

• Project/Area Number: 25860708
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Tohoku University (2014-2015); Nagoya University (2013)
• Principal Investigator: Udagawa Tsuyoshi 東北大学, 薬学研究科(研究院), 助教 (20644199)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ALS/FTLD / シナプス / RNA結合タンパク質 / mRNA代謝 / ALS・FTLD / 転写後遺伝子発現調節

Outline of Final Research Achievements

TDP-43 and FUS are RNA-binding proteins that are involved in neurodegenetive diseases, ALS/FTLD. We demonstrated that FUS knockdown neurons exhibited decreased number of mature synaptic spines and reduced synaptic transmission and that knockdown mice displayed disinhibition and social interaction deficits, reminiscent of FTLD symptoms. On the other hand, TDP-43 knockdown in the mouse hippocampus resulted in long-term memory deficits. Our results indicated that FUS controls the expression of GluA1, a subunit of one of the major glutamate receptors at synapses, by maintaining it mRNA stability. Moreover, behavioral abnormalities of FUS knockdown mice were ameliorated by exogenous expression of GluA1 subunit.

Research Products

• [Journal Article] FUSの最近の話題 (2016)
  • Author(s): 宇田川剛
  • Journal Title: 最新医学 3月増刊号 特集 認知症 Volume: 71 Pages: 538-543
• [Journal Article] FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization. (2015)
  • Author(s): Udagawa, T., Fujioka, Y., Tanaka, M., Honda, D., Yokoi, S., Riku, Y., Ibi, D., Nagai, T., Yamada, K., Watanabe, H., Katsuno, M., Inada, T., Ohno, K., Sokabe, M., Okado, H., Ishigaki S*., and Sobue, G.
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 7098-7098
  • DOI: 10.1038/ncomms8098
  • Peer Reviewed / Open Access
• [Journal Article] The ALS/FTLD-related RNA-binding proteins TDP-43 and FUS have common downstream RNA targets in cortical neurons (2013)
  • Author(s): Honda D, Ishigaki S, Iguchi Y, Fujioka Y, Udagawa T, Masuda A, Ohno K, Katsuno M, Sobue G.
  • Journal Title: FEBS Open Bio. Volume: 20 Issue: 1 Pages: 1-10
  • DOI: 10.1016/j.fob.2013.11.001
  • Peer Reviewed
• [Presentation] FUSはGluA1 mRNA安定性の調節を介してシナプス機能及びFTLD/ALS様行動を制御する (2015)
  • Author(s): 宇田川剛
  • Organizer: 第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] FUS regulates AMPA receptor function and ALS/FTLD-associated behaviors via GluR1 mRNA stabilization (2014)
  • Author(s): Tsuyoshi Udagawa, Yusuke Fujioka, Motoki Tanaka, Daiyu Honda, Satoshi Yokoi, Taku Nagai, Kiyofumi Yamada, Masahisa Katsuno, Masahiro Sokabe, Haruo Okado, Shinsuke Ishigaki, Gen Sobue
  • Organizer: CSHL meeting 'Translational Control'
  • Place of Presentation: Cold Spring Harbor
  • Year and Date: 2014-09-02 – 2014-09-06
• [Presentation] FUS はGluR1 mRNA の安定化を介してAMPA 受容体機能、及び ALS/FTLD 関連行動を制御する (2014)
  • Author(s): 宇田川剛、藤岡祐介、田中基樹、本田祐、横井聡、衣斐大祐、永井拓、山田清文、勝野雅央、曽我部正博、岡戸晴生、石垣診佑、祖父江元
  • Organizer: 第16回日本RNA学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-07-23 – 2014-07-25
• [Presentation] FUS depletion in adult causes behavioral abnormalities that mimic FTLD through post-transcriptional regulation of synaptic protein expression. (2013)
  • Author(s): Tsuyoshi Udagawa, Yusuke Fujioka, Daiyu Honda, Daisuke Ibi, Taku Nagai, Satoshi Yokoi, Masahisa Katsuno, Hayuo Okado, Shinsuke Ishigaki, Gen Sobue
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド（神戸市）