Analysis of cascade of neuronal cell death for TDP-43 in sporadic amyotrophic lateral sclerosis

• Project/Area Number: 23790977
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: The University of Tokyo
• Principal Investigator: YAMASHITA Takenari 東京大学, 大学院・医学系研究科, 特任研究員 (20431843)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: TDP-43 / ADAR2 / AMPA 受容体 / GluA2 / RNA 編集 / 筋萎縮性側索硬化症 / 神経細胞死 / Calpain / AMPA受容体 / RNA編集 / カルパイン

Research Abstract

We found that ADAR2-negative motor neurons in the spinal cord showed TDP-43 pathology in conditional ADAR2 knockout (AR2) mice, a mechanistic ALS model in which the ADAR2 gene is targeted in cholinergic neurons including motor neurons. Calpain, a Ca2+-dependent serine protease, was activated in motor neurons devoid of ADAR2 activity express abnormally Ca2+-permeable AMPA receptors that contain Q/R site-unedited GluA2. Moreover, calpain specifically cleaved TDP-43 into aggregation-prone fragments in the lysates of cultured cells.

Research Products

• [Journal Article] A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology (2012)
  • Author(s): Yamashita T, Hideyama T, Hachiga K, Teramoto S, Takano J, Iwata N, Saido TC, and Kwak S
  • Journal Title: Nat Commun Volume: 3 Issue: 1 Pages: 1307-1307
  • DOI: 10.1038/ncomms2303
  • Peer Reviewed
• [Journal Article] Co-occurrence of TDP-43 mislocalization with reduced RNA editing enzyme, ADAR2, in aged mouse motor neurons: implications for age-related acceleration of ALS (2012)
  • Author(s): Hideyama T, Teramoto S, Hachiga K, Yamashita T, Kwak S
  • Journal Title: PLoS One Volume: 7,(8) Issue: 8 Pages: e43469-e43469
  • DOI: 10.1371/journal.pone.0043469
  • Peer Reviewed
• [Journal Article] Profound downregulation of the RNA editing enzyme ADAR2 in ALS motor neurons (2012)
  • Author(s): Hideyama T, Yamashita Y, H Aizawa, Tsuji S,Kakita A, Takahashi H, Kwak S
  • Journal Title: Neurobiol Dis Volume: 45 Issue: 3 Pages: 1121-1128
  • DOI: 10.1016/j.nbd.2011.12.033
  • Peer Reviewed
• [Journal Article] RNA editing of the Q/R site of GluA2 in cultured cell lines expressing different levels of the RNA editing enzyme ADAR2 (2012)
  • Author(s): Yamashita T, Tadami C, Nishimoto Y, Hideyama T, Kimura D, Suzuki T,Kwak S
  • Journal Title: Neurosci Res Volume: 73 Issue: 1 Pages: 42-48
  • DOI: 10.1016/j.neures.2012.02.002
  • Peer Reviewed
• [Journal Article] Abnormal processing of TDP-43 does not regulate ADAR2 activity in cultured cell lines (2012)
  • Author(s): Yamashita T, Hideyama T, Teramoto S, Kwak S
  • Journal Title: Neurosci Res Volume: 73 Issue: 2 Pages: 153-160
  • DOI: 10.1016/j.neures.2012.02.015
  • Peer Reviewed
• [Presentation] 「RNA editing and ALS」 (2012)
  • Author(s): Kwak S, Hideyama T, Yamashita T
  • Organizer: 6th International symposium on nanomedicine
  • Place of Presentation: Shimane, Matsue
  • Year and Date: 2012-11-29
• [Presentation] RNA editing and ALS (2012)
  • Author(s): Kwak S., Hideyama T., Yamashita T.
  • Organizer: 6th International symposium on nanomedicine.
  • Place of Presentation: Shimane, Matsue, kunibikimesse
• [Presentation] Downregulation of RNA editing enzyme ADAR2 and sporadic ALS (2011)
  • Author(s): Hideyama, T., Yamashita, T., Aizawa, H. and Kwak, S
  • Organizer: The 22nd International Symposium on MND/ALS
  • Place of Presentation: Sydney, Australia.
• [Presentation] Abnormal GluR2 RNA editing and TDP-43 pathology in ALS motor neurons (2011)
  • Author(s): Yamashita, T., Hideyama, T., Hachiga, K., Teramoto, S. and Kwak, S
  • Organizer: 41st Annual Meeting Society for Neuroscience
  • Place of Presentation: Washington DC, USA.
• [Presentation] Abnormal GluR2 RNA editing and TDP-43 pathology in ALS motor neurons (2011)
  • Author(s): Yamashita, T., Hideyama, T., Hachiga, K., Teramoto, S. and Kwak, S
  • Organizer: 6th Brain Research conference "RNA binding proteins in neurological disease
  • Place of Presentation: Washington DC, USA
• [Presentation] ALS 運動ニューロンにお けるRNA編集異常とTDP-43 の病理. Abnormal GluR2 RNA editing and TDP-43 pathology in ALS motor neurons (2011)
  • Author(s): 山下雄也、日出山拓人、八賀康祐、寺本さやか、郭伸
  • Organizer: 第34回神経科学大会
  • Place of Presentation: 横浜
• [Presentation] ADAR2賦活物質のinvitroスクリーニングシステムの開発:孤発性ALS (2011)
  • Author(s): 山下雄也、寺本さやか、日出山拓人、郭伸
  • Organizer: 治療薬の探索.包括型脳科学研究推進支援ネットワーク夏のワークショップ
  • Place of Presentation: 神戸
• [Presentation] Inefficient RNA editing of GluA2 with ADAR2 downregulation and sporadic ALS (2011)
  • Author(s): Hideyama, T., Yamashita, T., Aizawa, H. and Kwak, S
  • Organizer: 8th IBRO World Congress of Neuroscience
  • Place of Presentation: Firenze, Itary
• [Presentation] AMPA受容体サブユニットGluR2のQ/R部位RNA編集率に及ぼす各種薬剤の効果 (2011)
  • Author(s): 澤田潤、相澤仁志、片山隆行、長谷部直幸、山下雄也、郭伸
  • Organizer: 第52回日本神経学会総会
  • Place of Presentation: 名古屋
• [Presentation] 孤発性ALSにおけるRNA編集異常のメカニズムと運動ニューロン死 (2011)
  • Author(s): 日出山拓人、山下雄也、相澤仁志、柿田明美、高橋均、辻省次、鈴木岳史、SeeburgPH,HiguchiM,高橋良輔、三澤日出巳、郭伸
  • Organizer: 第52回日本神経学会総会
  • Place of Presentation: 名古屋
• [Presentation] Inefficient RNA editing of GluA2 with ADAR2 downregulation and sporadic ALS. (2011)
  • Author(s): Hideyama, T., Yamashita, T., Aizawa, H. and Kwak, S.
  • Organizer: 8th IBRO World Congress of Neuroscience
  • Place of Presentation: Firenze, Itary.
• [Presentation] Abnormal GluR2 RNA editing and TDP-43 pathology in ALS motor neurons. (2011)
  • Author(s): Yamashita, T., Hideyama, T., Hachiga, K., Teramoto, S. and Kwak, S.
  • Organizer: 6th Brain Research conference "RNA binding proteins in neurological disease
  • Place of Presentation: Washington DC, USA.
• [Presentation] Abnormal GluR2 RNA editing and TDP-43 pathology in ALS motor neurons. (2011)
  • Author(s): Yamashita, T., Hideyama, T., Hachiga, K., Teramoto, S. and Kwak, S.
  • Organizer: 41st Annual Meeting Society for Neuroscience
  • Place of Presentation: Washington DC, USA.
• [Presentation] Downregulation of RNA editing enzyme ADAR2 and sporadic ALS. (2011)
  • Author(s): Hideyama, T., Yamashita, T., Aizawa, H. and Kwak, S.
  • Organizer: The 22nd International Symposium on MND/ALS
  • Place of Presentation: Sydney, Australia.
• [Presentation] AMPA 受容体サブユニットGluR2 のQ/R 部位RNA 編集率に及ぼす各種薬剤の効果. (2011)
  • Author(s): 澤田潤、相澤仁志、片山隆行、長谷部直幸、山下雄也、郭 伸.
  • Organizer: 第52 回日本神経学会総会
  • Place of Presentation: 名古屋
• [Presentation] 孤発性ALS におけるRNA 編集異常のメカニズムと運動ニューロン死. (2011)
  • Author(s): 日出山拓人、山下雄也、相澤仁志、柿田明美、高橋均、辻省次、鈴木岳史、Seeburg PH, Higuchi M, 高橋良輔、三澤日出巳、郭 伸.
  • Organizer: 第5２回日本神経学会総会
  • Place of Presentation: 名古屋
• [Presentation] ADAR2 賦活物質のin vitro スクリーニングシステムの開発：孤発性ALS 治療薬の探索. (2011)
  • Author(s): 山下雄也、寺本さやか、日出山拓人、郭 伸.
  • Organizer: 包括型脳科学研究推進支援ネットワーク 夏のワークショップ
  • Place of Presentation: 神戸
• [Presentation] ALS 運動ニューロンにおけるRNA編集異常とTDP-43 の病理. Abnormal GluR2 RNA editing and TDP-43 pathology in ALS motor neurons. (2011)
  • Author(s): 山下雄也、日出山拓人、八賀康祐、寺本さやか、郭 伸.
  • Organizer: 第34 回神経科学大会
  • Place of Presentation: 横浜.
• [Remarks]
  • URL: http://square.umin.ac.jp/teamkwak/
• [Remarks] Todai-Research（筋萎縮性側索硬化症に特異的病理変化の謎解明）
  • URL: http://www.u-tokyo.ac.jp/ja/todai-research/research-news/mechanism-for-tdp-43-pathology-in-als/
• [Remarks] 東京大学医学部プレスリリース（筋萎縮性側索硬化症に特異的病理変化の謎解明）
  • URL: http://www.m.u-tokyo.ac.jp/news/2012press.html#20121219-2
• [Remarks] 東京大学大学院医学系研究科疾患生命工学センター臨床医工学部門 郭研究室
  • URL: http://square.umin.ac.jp/teamkwak/