Identification of therapeutic targets for ALS by screening for TDP-43 and FUS associated molecules

• Project/Area Number: 23659452
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: SOBUE Gen 名古屋大学, 医学系研究科, 教授 (20148315)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 筋萎縮性側索硬化症 / ALS / FUS / 小胞体ストレス / 改変GFP / 検知システム / 神経変性疾患モデル細胞

Research Abstract

Mouse primary cortical neurons were silenced with FUS by introducing lentivirus encoding shRNA against FUS gene. We next established the FUS-regulated transcriptome profiles of primary neurons using exon-sensitive microarrays and identified that FUS regulated the alternative splicing of Mapt exon10. This alternative splicing event results in three-repeats (RD3) and four-repeats (RD4) Tau isoform production and the ratio of RD4/RD3 was increased when FUS was silenced in neurons. Morphological abnormality of neurite was observed in FUS-silenced primary neurons and it was rescued bysilencing of RD4. These findings suggest that RD4 could be a therapeutic target for ALS treatment.

Research Products

• [Journal Article] Loss of TDP-43 causes age-dependent progressive motor neuron degeneration (2013)
  • Author(s): Iguchi Y
  • Journal Title: Brain Volume: 136 Issue: 5 Pages: 1371-1382
  • DOI: 10.1093/brain/awt029
  • Peer Reviewed / Open Access
• [Journal Article] Loss of TDP-43 causes age-dependent progressive motor neuron degeneration (2013)
  • Author(s): Iguchi Y, Katsuno M, Niwa JI, Takagi S, Ishigaki S, Ikenaka K, Kawai K, Watanabe H, Yamanaka K, Takahashi R, Misawa H, Sasaki S, Tanaka F, Sobue G
  • Journal Title: Brain Volume: epub
  • Peer Reviewed
• [Journal Article] Oxidative stress induced by glutathione depletion reproduces pathological modifications of TDP-43 linked to TDP-43 proteinopathies. (2012)
  • Author(s): Iguchi Y,Katsuno M,Takagi S.Ishigaki S,Niwa JI,Hasegawa M,Tanaka F,Sobue G
  • Journal Title: Neurobiol Dis Volume: 45 Issue: 3 Pages: 862-870
  • DOI: 10.1016/j.nbd.2011.12.002
  • Peer Reviewed
• [Journal Article] Position-dependent FUS-RNA interactions regulate alternative splicing events and transcriptions. (2012)
  • Author(s): Ishigaki S, Masuda A, Fujioka Y, Iguchi Y, Katsuno M, Shibata A, Urano F, Sobue G, Ohno K
  • Journal Title: Sci Rep Volume: 2 Issue: 1 Pages: 529-529
  • DOI: 10.1038/srep00529
  • Peer Reviewed
• [Presentation] Comparison of Fus-regulating gene expression and alternative splicing profiles among different cell lineages in the central nervous system (2012)
  • Author(s): Shinsuke Ishigaki, Yusuke Fujioka, Akio Masuda, Yohei Iguchi, Masahisa Katsuno, Kinji Ohno, and Gen Sobue
  • Organizer: The 42nd Society for Neuroscience annual meeting
  • Place of Presentation: New Orleans, LA USA
• [Presentation] FUS regulates alternative splicing patterns of Mapt by cooperating with PSF/SFPQ in neurons: a novel link between FUS and Tau in the pathogenesis of ALS and FTLD (2012)
  • Author(s): Shinsuke Ishigaki, Yusuke Fujioka, and Gen Sobue
  • Organizer: 6th International Symposium of Nanomedicine
  • Place of Presentation: Matsue, Japan
• [Presentation] ALS における FUS/TLSの質的機能喪失と病態:FUS/TLS の核内高分子複合体の機能解析から (2012)
  • Author(s): 石垣 診祐、藤岡 祐介、田中 章景、祖父江 元
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京
• [Presentation] 族性 ALS 原因遺伝子 FUS/TLS ノックダウンに伴う選択的 splicing 変化 (2012)
  • Author(s): 藤岡 祐介、石垣 診祐、増田 章男、大野 欽司、祖父江 元
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京
• [Presentation] FUS regulates alternative splicing patterns of Mapt by cooperating with PSF/SFPQ: a novel link between FUS and Tau in the pathogenesis of ALS and FTLD (2012)
  • Author(s): Shinsuke Ishigaki, Yusuke Fujioka, Yohei Okada, Akio Masuda, Kinji Ohno, and Gen Sobue
  • Organizer: The 35th annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: Nagoya, Japan
• [Presentation] Comparison of Fus-regulating gene expression and alternative splicing profiles among different primary cells in central nervous system (2012)
  • Author(s): Yusuke Fujioka, Shinsuke Ishigaki, Akio Masuda, Kinji Ohno, and Gen Sobue
  • Organizer: The 35th annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: Nagoya, Japan
• [Presentation] Comparison of Fus-regulating gene expression and alternative splicing profiles among different cell lineages in the central nervous system (2012)
  • Author(s): Shinsuke Ishigaki, Yusuke Fujioka, Akio Masuda, Yohei Iguchi, Masahisa Katsuno, Kinji Ohno, and Gen Sobue
  • Organizer: The 42nd Society for Neuroscience annual meeting
  • Place of Presentation: New Orleans, LA
• [Presentation] ALSにおけるFUS/TLSの質的機能喪失と病態：FUS/TLSの核内高分子複合体の機能解析から (2012)
  • Author(s): 石垣 診祐、 藤岡 祐介、 田中 章景、 祖父江 元
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京
• [Presentation] 家族性ALS原因遺伝子FUS/TLSノックダウンに伴う選択的splicing変化 (2012)
  • Author(s): 藤岡 祐介、石垣 診祐、増田 章男、大野 欽司、祖父江 元
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京
• [Presentation] FUS regulates alternative splicing patterns of Mapt by cooperating with PSF/SFPQ: a novel link between FUS and Tau in the pathogenesis of ALS and FTLD. (2012)
  • Author(s): Shinsuke Ishigaki, Yusuke Fujioka, Yohei Okada, Akio Masuda, Kinji Ohno, and Gen Sobue
  • Organizer: The 35th annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 名古屋
• [Presentation] Comparison of Fus-regulating gene expression and alternative splicing profiles among different primary cells in central nervous system (2012)
  • Author(s): Yusuke Fujioka, Shinsuke Ishigaki, Akio Masuda, Kinji Ohno, and Gen Sobue
  • Organizer: The 35th annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 名古屋
• [Presentation] Quality loss of FUS function is involved in the pathogenesis of ALS. (2011)
  • Author(s): Shinsuke Ishigaki, Yusuke Fujioka, and Gen Sobue
  • Organizer: The 41th Society for Neuroscience annual meeting.
  • Place of Presentation: Washington, DC.
• [Presentation] Profiles of differential gene expression and alternative splicing in FUS knock-down primary motor neurons. (2011)
  • Author(s): Yusuke Fujioka, Shinsuke Ishigaki, and Gen Sobue
  • Organizer: The 41th Society for Neuroscience annual meeting
  • Place of Presentation: Washington, DC.
• [Presentation] Quality loss of FUS function is involved in the pathogenesis of ALS. (2011)
  • Author(s): Shinsuke Ishigaki, Yusuke Fujioka, and Gen Sobue
  • Organizer: The 3rd Global COE International Symposium .
  • Place of Presentation: ミッドランドホール Nagoya, Japan.
• [Presentation] 運動ニューロンにおけるALS関連変異FUS/TLSの機能障害 (2011)
  • Author(s): 石垣診祐、藤岡祐介、田中章景、祖父江元
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋国際会議場 名古屋
• [Presentation] 分化運動ニューロンを用いたFUS/TLSノックダウンモデルの作成と機能解析 (2011)
  • Author(s): 藤岡祐介、石垣診祐、祖父江元
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋国際会議場 名古屋