Elucidation of the molecular mechanism of ALS pathogenesis mediated by cytoplasmic RNA.

• Project/Area Number: 15K18365
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Tohoku University
• Principal Investigator: NAKAGAWA Tadashi 東北大学, 医学系研究科, 助教 (30707013)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 筋萎縮性側索硬化症（ALS） / TDP-43 / 細胞内凝集体形成 / RNA / RNA分解酵素 / ALS / RNase

Outline of Final Research Achievements

Nearly all of the amyotrophic lateral sclerosis (ALS) patients contain cytoplasmic aggregation of TDP-43 in their neuronal tissues. Although aggregated TDP-43 was shown to contribute to the ALS pathogenesis, the molecular mechanism by which TDP-43 forms cytoplasmic aggregation are not fully understood. We found that the mutation of TDP-43 which disrupted the association with RNA significantly reduced cytoplasmic aggregation. Furthermore, TDP-43 fused with RNase exhibited the resistance to aggregation formation. These results revealed that RNA is critical for TDP-43 to form cytoplasmic aggregation and offered the novel therapeutic strategy for the treatment of ALS.

Research Products

• [Journal Article] Ubiquitylation of Ku80 by RNF126 Promotes Completion of Nonhomologous End Joining-Mediated DNA Repair. (2017)
  • Author(s): Ishida N, Nakagawa T, Iemura SI, Yasui A, Shima H, Katoh Y, Nagasawa Y, Natsume T, Igarashi K, Nakayama K.
  • Journal Title: Mol Cell Biol Volume: 37 Issue: 4
  • DOI: 10.1128/mcb.00347-16
  • Peer Reviewed
• [Journal Article] The SCFβ-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis. (2017)
  • Author(s): Shimizu K, Fukushima H, Ogura K, Lien EC, Nihira NT, Zhang J, North BJ, Guo A, Nagashima K, Nakagawa T, Hoshikawa S, Watahiki A, Okabe K, Yamada A, Toker A, Asara JM, Fukumoto S, Nakayama KI, Nakayama K, Inuzuka H, Wei W.
  • Journal Title: Sci Signal. doi: 10.1126/scisignal.aah4117. Volume: 10 Issue: 460 Pages: 1-15
  • DOI: 10.1126/scisignal.aah4117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protein monoubiquitylation: targets and diverse functions (2015)
  • Author(s): Nakagawa T, Nakayama K
  • Journal Title: Genes to cells Volume: 7 Issue: 7 Pages: 543-562
  • DOI: 10.1111/gtc.12250
  • Peer Reviewed / Open Access
• [Journal Article] S6 Kinase- and beta-TrCP2-Dependent Degradation of p19Arf Is Required for Cell Proliferation (2015)
  • Author(s): Nakagawa T, Araki T, Nakagawa M, Hirao A, Unno M, Nakayama K
  • Journal Title: Molecular and cellular biology Volume: 20 Issue: 20 Pages: 3517-3527
  • DOI: 10.1128/mcb.00343-15
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Interplay of MYC oncogene and ubiquitin-proteasomal degradation of a TFIID component in proliferation switch. (2017)
  • Author(s): Tadashi Nakagawa, Masaki Hosogane, Ryo Funayama, Keiko Nakayama.
  • Organizer: NIH-Tohoku University-International Symposium
  • Place of Presentation: 東北大学星陵会館（宮城県仙台市）
  • Year and Date: 2017-02-17
  • Invited
• [Presentation] ユビキチン化によるFACT複合体の機能制御 (2016)
  • Author(s): 諸星茜、中川直、中山啓子
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-12-01
• [Presentation] Molecular analysis of Amyotrophic Lateral Sclerosis associated Cyclin F mutants. (2016)
  • Author(s): Yujiao Yu, Akane Morohoshi, Tadashi Nakagawa, Keiko Nakayama.
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-12-01
• [Presentation] Reactivation of cell proliferation by continuous TGF-β treatment. (2016)
  • Author(s): Tadashi Nakagawa, Masaki Hosogane, Ryo Funayama, Keiko Nakayama.
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] セルトリ細胞特異的β-TrCPノックアウトマウスの解析 (2015)
  • Author(s): 諸星茜、中川直、中野星児、中山啓子
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] TGF-β刺激によるTFIID構成因子TAF7の分解とその役割の解明 (2015)
  • Author(s): 中川直、細金正樹、舟山亮、中山啓子
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Remarks] 東北大学がん医学コアセンター細胞増殖制御分野
  • URL: http://www.devgen.med.tohoku.ac.jp/index.html