ALS and TDP-43: Dose the splicing failure underlie the pathogenesis of ALS?

• Project/Area Number: 23240049
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Niigata University
• Principal Investigator: HITOSHI Takahashi 新潟大学, 脳研究所, 教授 (90206839)
• Co-Investigator(Kenkyū-buntansha): TOYOSHIMA Yasuko 新潟大学, 脳研究所, 准教授 (20334675) ; ONODERA Osamu 新潟大学, 脳研究所, 准教授 (20303167)
• Co-Investigator(Renkei-kenkyūsha): KUWANO Ryozo 新潟大学, 脳研究所, 教授 (20111734) ; SAKIMURA Kenji 新潟大学, 脳研究所, 教授 (40162325) ; KAKITA Akiyoshi 新潟大学, 脳研究所, 教授 (80281012) ; YOKOYAMA Minesuke 新潟大学, 脳研究所, 教授 (40090930)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥45,890,000 (Direct Cost: ¥35,300,000、Indirect Cost: ¥10,590,000); Fiscal Year 2013: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2012: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2011: ¥29,250,000 (Direct Cost: ¥22,500,000、Indirect Cost: ¥6,750,000)
• Keywords: 脳神経疾患 / 神経病理学 / 神経変性疾患 / 筋萎縮性側索硬化症 / TDPー４３ / TDP-43 / ALS / スプライシング / ナンセンス / mRNA分解機構 / 欠損マウス / ミニジーン / スプライシング因子

Research Abstract

Amyotrophic lateral sclerosis (ALS) is fatal neurodegenerative disease. For a development of therapeutic methods for this disease, we investigated the splicing variants of TDP-43, and its own function associated with splicing for other genes. We found that THP-43 has menu splicing variants, and investigate the mechanism how splicing factors influence this splicing. In addition, we found some of the mutation with ALS10, which is caused by a mutation in TDP-43, affects the efficiency of its own splicing. These findings may open new avenue for the investigation of the pathogenesis of ALS.

Research Products

• [Journal Article] TDP-43 pathology in polyglutamine diseases : with reference to amyotrophic lateral sclerosis (2014)
  • Author(s): Toyoshima Y, Takahashi H
  • Journal Title: Neuropathology Volume: 34 Pages: 77-82
  • Peer Reviewed
• [Journal Article] Decreased number of Gemini of coiled bodies and U12 snRNA level in amyotrophic lateral sclerosis (2013)
  • Author(s): Ishihara T, Ariizumi Y, Shiga A, Kato T, Tan CF, Sato T, Miki Y, Yokoo M, Fujino T, Koyama A, Yokoseki A, Nishizawa M, Kakita A, Takahashi H, Onodera O
  • Journal Title: Hum Mol Genet Volume: 22 Pages: 4136-4147
  • Peer Reviewed
• [Journal Article] Sporadic ALS with compound heterozygous mutation in the SQSTM1 gene (2013)
  • Author(s): Shimizu H, Toyoshima Y, Shiga A, Yokoseki A, Arakawa K, Sekine Y, Shimohata T, Ikeuchi T, Nishizawa M, Kakita A, Onodera O, Takahashi H
  • Journal Title: Acta Neuropathol Volume: 126 Pages: 453-459
  • Peer Reviewed
• [Journal Article] Transportin 1 accumulates in FUS inclusions in adult-onset ALS without FUS mutation (2013)
  • Author(s): Takeuchi R, Toyoshima Y, Tada M, Shiga A, Tanaka H, Shimohata M, Kimura K, Morita T, Kakita A, Nishizawa M, Takahashi H
  • Journal Title: Neuropathol Appl Neurobiol Volume: 39 Pages: 580-584
  • Peer Reviewed
• [Journal Article] Dropped head syndrome in amyotrophic lateral sclerosis (2013)
  • Author(s): Uemura M, Kosaka T, Shimohata T, Ishikawa M, Nishihira Y, Toyoshima Y, Yanagawa K, Kawachi I, Takahashi H, Nishizawa M
  • Journal Title: Amyotroph Lateral Scler Frontotemporal Degener Volume: 14 Pages: 232-233
  • Peer Reviewed
• [Journal Article] Japanese amyotrophic lateral sclersois patients with GGGGCC hexanucleotide repeat expansion in C90RF72 (2013)
  • Author(s): Konno T, Shiga A, Tsujino A, Sugai A, Kato T, Kanai K, Yokoseki A, Eguchi H, Kuwabara S, Nishizawa M, Takahashi H, Onodera O
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 84 Pages: 398-401
  • Peer Reviewed
• [Journal Article] A fatal neuromuscular disease in an adult patient after poliomyelitis in early childhood : consideration of the pathology of post-polio syndrome (2013)
  • Author(s): Kosaka T, Kuroha Y, Tada M, Hasegawa A, Tani T, Matsubara N, Koike R, Toyoshima Y, Takahashi H
  • Journal Title: Neuropathology Volume: 33 Pages: 93-101
  • Peer Reviewed
• [Journal Article] A fatal neuromuscular disease in an adult patient after poliomyelitis in early childhood: consideration of the pathology of post-polio syndrome. (2013)
  • Author(s): Kosaka T, Kuroha Y, Tada M, Hasegawa A, Tani T, Matsubara N, Koike R, Toyoshima Y, Takahashi H
  • Journal Title: Neuropathology Volume: 33 Issue: 1 Pages: 93-101
  • DOI: 10.1111/j.1440-1789.2012.01327.x
  • Peer Reviewed
• [Journal Article] Japanese amyotrophic lateral sclerosis patients with GGGGCC hexanucleotide repeat expansion in C9ORF72. (2013)
  • Author(s): Konno T
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 84(4) Issue: 4 Pages: 398-401
  • DOI: 10.1136/jnnp-2012-302272
  • Peer Reviewed
• [Journal Article] Dropped head syndrome in amyotrophic lateral sclerosis. (2013)
  • Author(s): Uemura M, Kosaka T, Shimohata T, Ishikawa M, Nishihira Y, Toyoshima Y, Yanagawa K, Kawachi I, Takahashi H, Nishizawa M
  • Journal Title: Amyotroph Lateral Scler Frontotemporal Degener Volume: 14 Issue: 3 Pages: 232-233
  • DOI: 10.3109/17482968.2012.727424
  • Peer Reviewed
• [Journal Article] ITIH4 and Gpx3 are potential biomarkers for amyotrophic lateral sclerosis. (2013)
  • Author(s): Tanaka H.. Shimazawa M., Takata M., Kaneko H., Tsuruma K., Ikeda T., Warita H., Aoki M., Yamada M., Takahashi H., Hozumi I., Minatsu H., Inuzuka T. and Hara H.
  • Journal Title: Journal of Neurology Volume: (Epub ahead of print) Issue: 7 Pages: 1782-1797
  • DOI: 10.1007/s00415-013-6877-3
  • Peer Reviewed
• [Journal Article] Transportin 1accumulates in FUS inclusions inadult-onset ALS without FUS mutation (2013)
  • Author(s): Takeuchi R, Toyoshima Y, Tada M, ShigaA, Tanaka H, Shimohata M, Kimura K,Morita T, Kakita A, Nishizawa M,Takahashi H
  • Journal Title: Neuropathol Appl Neurobiol Volume: Epub Issue: 5 Pages: 580-584
  • DOI: 10.1111/nan.12022
  • Peer Reviewed
• [Journal Article] Sporadic ALS with compound heterozygous mutation in the SQSTM1 gene. (2013)
  • Author(s): Shimizu H, Toyoshima Y, Shiga A, Yokoseki A, Arakawa K, Sekine Y, Shimohata T, Ikeuchi T, Nishizawa M, Kakita A, Onodera O, Takahashi H
  • Journal Title: Acta Neuropathol Volume: 126 Issue: 3 Pages: 453-459
  • DOI: 10.1007/s00401-013-1150-5
  • Peer Reviewed
• [Journal Article] Decreased number of Gemini of coiled bodies and U12 snRNA level in amyotrophic lateral sclerosis. (2013)
  • Author(s): Ishihara T, Ariizumi Y, Shiga A, et al ;
  • Journal Title: Human Molecular Genetics Volume: 22 Issue: 20 Pages: 4136-4147
  • DOI: 10.1093/hmg/ddt262
  • Peer Reviewed
• [Journal Article] ITIH4 and Gpx3 are potential biomarkers for amyotrophic lateral sclerosis. (2013)
  • Author(s): Tanaka H
  • Journal Title: J Neurol Volume: epub
  • Peer Reviewed
• [Journal Article] Keap1 is localized in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases (2013)
  • Author(s): Tanji K, Maruyama A, Odagiri S, Mori F, Itoh K, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: J Neuropathol Exp Neurol Volume: 72 Issue: 1 Pages: 18-28
  • DOI: 10.1097/nen.0b013e31827b5713
  • Peer Reviewed
• [Journal Article] Coexistence of Huntington's disease and amyotrophic lateral sclerosis : a clinicopathologic study (2012)
  • Author(s): Tada M, Coon EA, Osmand AP, Kirby PA, Martin W, Wieler M, Shiga A, Shirasaki H, Tada M, Makifuchi T, Yamada M, Kakita A, Nishizawa M, Takahashi H, Paulson HL
  • Journal Title: Acta Neuropathol Volume: 124 Pages: 749-760
  • Peer Reviewed
• [Journal Article] Alterarion of POLDIP3 splicing associated with loss of function of TDP-43 in tissues affected with ALS (2012)
  • Author(s): Shiga A, Ishihara T, Miyashita A, Kuwabara M, Kato T, Watanabe N, Yamahira A, Kondo C, Yokoseki A, Takahashi M, Kuwano R, Kakita A, Nishizawa M, Takahashi H, Onodera O
  • Journal Title: PLoS One Volume: 7
  • Peer Reviewed
• [Journal Article] Primary lateral sclerosis : upper-motor-predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration - immunohistochemical and biochemical analyses of TDP-43 (2012)
  • Author(s): Kosaka T, Fu YJ, Shiga A, Ishidaira H, Tan CF, Tani T, Koike R, Onodera O, Nishizawa M, Kakita A, Takahashi H
  • Journal Title: Neuropathology Volume: 32 Pages: 373-384
  • Peer Reviewed
• [Journal Article] Co-occurrence of argyrophilic grain disease in sporadic amyotrophic lateral sclerosis (2012)
  • Author(s): Soma K, Fu YJ, Wakabayashi K, Onodera O, Kakita A, Takahashi H
  • Journal Title: Neuropathol Appl Neurobiol Volume: 38 Pages: 54-60
  • Peer Reviewed
• [Journal Article] Alteration of P0LDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS (2012)
  • Author(s): Shiga A, et al ;
  • Journal Title: PLoS ONE Volume: 7(8) Issue: 8 Pages: e43120-e43120
  • DOI: 10.1371/journal.pone.0043120
  • Peer Reviewed
• [Journal Article] The potential of GPNMB as novel neuroprotective factor in amyotrophic lateral sclerosis. (2012)
  • Author(s): Tanaka H.. Shimazawa M., Kimura M., Takata M., Tsuruma K, Yamada M., Takahashi H., Hozumi I., Niwa J., Iguchi Y., Nikawa T., Sobue G., Inuzuka T. and Hara H.
  • Journal Title: Scientific Reports Volume: 2 Issue: 1 Pages: 573-573
  • DOI: 10.1038/srep00573
  • Peer Reviewed
• [Journal Article] Coexistence of Huntington's disease and amyotrophic lateral sclerosis: a clinicopathologic study. (2012)
  • Author(s): Tada M
  • Journal Title: Acta Neuropathol. Volume: 124(5) Issue: 5 Pages: 749-60
  • DOI: 10.1007/s00401-012-1005-5
  • Peer Reviewed
• [Journal Article] Molecular pathology and genetic advances in amyotrophic lateral sclerosis : an emerging molecular pathway and the significance of glial pathology (2011)
  • Author(s): Ince PG, Highley JR, Kirby J, Wharton SB, Takahashi H, Strong MJ, Shaw PJ
  • Journal Title: Acta Neuropathol Volume: 122 Pages: 657-671
  • Peer Reviewed
• [Journal Article] Spinocerebellar ataxia type 2 (SCA2) is associated with TDP-43 pathology (2011)
  • Author(s): Toyoshima Y, Tanaka H, Shimohata M, Kimura K, Morita T, Kakita A, Takahashi H
  • Journal Title: Acta Neuropathol Volume: 122 Pages: 375-378
  • Peer Reviewed
• [Journal Article] Enhancement of native and phosphorylated TDP-43 immunoreactivity by proteinase K treatment following autoclave heating (2011)
  • Author(s): Mori F, Tanji K, Kakita A, Takahashi H, Wakabayashi K
  • Journal Title: Neuropathology Volume: 31 Pages: 401-404
  • Peer Reviewed
• [Journal Article] Survival motor neuron (SMN) protein in the spinal anterior horn cells of patients with sporadic amyotrophic lateral sclerosis (2011)
  • Author(s): Piao Y, Hashimoto T, Takahama S, Kakita A, Komori T, Morita T, Takahashi H, Mizutani T, Oyanagi K
  • Journal Title: Brain Res Volume: 1372 Pages: 152-159
  • NAID: 120007110507
  • Peer Reviewed
• [Journal Article] Primary lateral sclerosis : Upper-motor-predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration-immunohistochemical and biochemical analyses of TDP-43 (2011)
  • Author(s): Kosaka T, Fu YJ, Shiga A, Ishidaira H, Tan CF, Tani T, Koike R, Onodera O, Nishizawa M, Kakita A, Takahashi H
  • Journal Title: Neuropathology. 2011 Volume: 32 Issue: 4 Pages: 373-384
  • DOI: 10.1111/j.1440-1789.2011.01271.x
  • Peer Reviewed
• [Presentation] 多系統に変性をきたした孤発性ALS の人工呼吸管理による長期生存例 (2013)
  • Author(s): 木村正志, 瀬戸牧子, 岩永圭介, 辻畑光宏, 佐藤 聡, 柿田明美, 高橋 均
  • Organizer: 第54回日本神経病理学会
  • Place of Presentation: 東京
  • Year and Date: 2013-04-26
• [Presentation] 筋萎縮性側索硬化症の大脳皮質におけるTDP-43 の組織学的および生化学的解析 (2013)
  • Author(s): 竹内亮子, 志賀 篤, 他田真理, 今野卓也, 豊島靖子, 柿田明美, 小野寺理, 西澤正豊, 高橋 均
  • Organizer: 第54回日本神経病理学会
  • Place of Presentation: 東京
  • Year and Date: 2013-04-25
• [Presentation] 筋萎縮性側索硬化症の大脳皮質におけるTDP-43の組織学的および生化学的解析. (2013)
  • Author(s): 竹内亮子, 志賀 篤, 他田真理,今野卓也, 豊島靖子, 柿田明美, 小野寺 理, 西澤正豊, 高橋 均
  • Organizer: 第54回日本神経病理学会
  • Place of Presentation: 東京
• [Presentation] 多系統に変性をきたした孤発性ALSの人工呼吸管理による長期生存例. (2013)
  • Author(s): 木村正志, 瀬戸牧子, 岩永圭介, 辻畑光宏, 佐藤 聡, 柿田明美, 高橋 均
  • Organizer: 第54回日本神経病理学会
  • Place of Presentation: 東京
• [Presentation] TDP-43 Q343Rノックインマウスの生化学的，神経病理学的解析 (2013)
  • Author(s): 廣川祥子
  • Organizer: 第118回日本解剖学会総会
  • Place of Presentation: 香川
• [Presentation] レーザーマイクロダイセクション法による脊髄運動ニューロンの単離方法の確立 (2013)
  • Author(s): 近藤千草
  • Organizer: 第118回日本解剖学会総会
  • Place of Presentation: 香川
• [Presentation] Neuropathology of amyotrophic lateral sclerosis - Discovery of TDP-43 and after that - (2012)
  • Author(s): Takahashi H
  • Organizer: Seoul Neuropathology Forum - The Neuropathology Study Group of the Korean Society of Pathologists
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2012-12-08
  • Invited
• [Presentation] Reduction of U12 snRNAs in nervous tissues with TDP-43 pathology in amyotrophic lateral sclerosis (2012)
  • Author(s): Ishihara T, Shiga A, Yokoseki A, Kakita A, Nishizawa M, Takahashi H, Onodera O
  • Organizer: Society For Neuroscience 2012
  • Place of Presentation: New Orleans,USA
  • Year and Date: 2012-10-17
• [Presentation] 上位運動ニューロンの組織変性が下位のそれに比し高度であったALS剖検例の検討 (2012)
  • Author(s): 他田真理, 柿田明美, 志賀 篤, 黒羽泰子, 小池亮子, 樋口真也, 森 茂, 付永娟, 豊島靖子, 小柳清光, 西澤正豊,高橋 均
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 新潟
  • Year and Date: 2012-06-30
• [Presentation] 下位運動神経細胞にp62 陽性/TDP-43 陰性の胞体内封入体を認めたALS の一例 (2012)
  • Author(s): 清水 宏, 豊島靖子, 荒川恵子, 関根有美, 横尾明男, 下畑享良, 池内 健, 志賀 篤, 西澤正豊, 高橋 均
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 新潟
  • Year and Date: 2012-06-30
• [Presentation] 比較的長期に経過したALS-FUS の一剖検例 (2012)
  • Author(s): 竹内亮子, 豊島靖子, 田中 一, 遠藤耕太郎, 森田 俊, 志賀 篤, 西澤正豊,高橋 均
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 新潟
  • Year and Date: 2012-06-30
• [Presentation] ALS患者神経組織ではスプライシング関連機能性RNAが低下する (2012)
  • Author(s): 石原智彦,志賀篤,横尾麻衣子,有泉優子,横関明男,譚春鳳,柿田明美,西澤正豊,高橋 均,小野寺理
  • Organizer: 第53回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-05-23
• [Presentation] Primary lateral sclerosis : an immunohistochemical and biochemical study of pathological TDP-43 in two cases (2012)
  • Author(s): Kosaka T, Fu YJ, Shiga A, Onodera O, Nishizawa M, Kakita A, Takahashi H
  • Organizer: The 8th International Conference on Frontotemporal Dementias
  • Place of Presentation: Manchester, UK
• [Presentation] nc9FTD/ALS is rare in Japanese familial and sporadic amyotrophic lateral sclerosis patiets (2012)
  • Author(s): Konno T
  • Organizer: Neuorscience 2012
  • Place of Presentation: New Orlens
• [Presentation] Reduction of U12 snKonno TRNAs in nervous tissues with TDP-43 pathology in amyotrophic lateral sclerosis (2012)
  • Author(s): Ishihara T
  • Organizer: Neuorscience 2012
  • Place of Presentation: New Orleans
• [Presentation] ALS患者神経組織ではスプライシング関連機能性RNAが低下する (2012)
  • Author(s): 石原智彦
  • Organizer: 第53回 日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] RNA代謝からTDP-43 proteinopathyの病態に迫る (2012)
  • Author(s): 小野寺理
  • Organizer: 第53回 神経病理学会総会学術研究会
  • Place of Presentation: 新潟
  • Invited
• [Presentation] 本邦の9FTD/ALSのまとめと展望 (2012)
  • Author(s): 小野寺理
  • Organizer: 厚労省神経変性疾患に関する調査研究班 平成24年度ワークショップ
  • Place of Presentation: 東京
  • Invited
• [Presentation] 筋萎縮性側索硬化症の克服を目指して (2012)
  • Author(s): 小野寺理
  • Organizer: 新潟医学会特別講演
  • Place of Presentation: 新潟
  • Invited
• [Presentation] 筋萎縮性側索硬化症におけるTDP-43とBunina小体の関わり (2012)
  • Author(s): 森 文秋
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 新潟
• [Presentation] 下位運動神経細胞にp62陽性/TDP-43陰性の胞体内封入体を認めたALSの一例 (2012)
  • Author(s): 清水 宏
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 新潟
• [Presentation] 比較的長期に経過したALS-FUSの一剖検例 (2012)
  • Author(s): 竹内亮子
  • Organizer: 第53回日本神経病理学会
  • Place of Presentation: 新潟
• [Presentation] Primary lateral sclerosis: an immunohistochemical and biochemical study of pathological TDP-43 in two cases (2012)
  • Author(s): Kosaka T
  • Organizer: The 8th International Conference on Frontotemporal Dementias
  • Place of Presentation: Manchester, UK
• [Presentation] Neuropathology of amyotrophic lateral sclerosis – Discovery of TDP-43 and after that - (2012)
  • Author(s): Takahashi H
  • Organizer: Seoul Neuropathology Forum – The Neuropathology Study Group of the Korean Society of Pathologists
  • Place of Presentation: Seoul, Korea
  • Invited
• [Presentation] C9ORF72変異を有するALSの１剖検例 (2012)
  • Author(s): 高橋 均
  • Organizer: 厚労省神経変性疾患に関する調査研究班 平成24年度ワークショップ
  • Place of Presentation: 東京
  • Invited
• [Presentation] 筋萎縮性側索硬化症における嗜銀顆粒性認知症の共存について (2011)
  • Author(s): 相馬健一, 付 永娟, 若林孝一, 小野寺理, 柿田明美, 高橋 均
  • Organizer: 第52回日本神経病理学会京都
  • Place of Presentation: 京都
  • Year and Date: 2011-06-04
• [Presentation] 筋萎縮性側索硬化症における嗜銀顆粒性認知症の共存について (2011)
  • Author(s): 相馬健一
  • Organizer: 第52回日本神経病理学会総会学術研究会
  • Place of Presentation: 京都テルサ(京都市)
  • Year and Date: 2011-06-04
• [Presentation] 熱処理後proteinase K処理によるTDP-43免疫染色性の増強 (2011)
  • Author(s): 森文秋
  • Organizer: 第52回日本神経病理学会総会学術研究会
  • Place of Presentation: 京都テルサ(京都市)
  • Year and Date: 2011-06-04
• [Presentation] ALS : a multisystem neuronal-glial proteinopathy of TDP43 (2011)
  • Author(s): Takahashi H
  • Organizer: The 7th Asia Pacific IAP (APIAP 2011)
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2011-05-24
  • Invited
• [Presentation] Amyotrophic lateral sclerosis : a multisystem neuro-glial proteinopathy of TDP-43 (2011)
  • Author(s): Takahashi H
  • Organizer: The 7th Aisia Pacific IAP (International Academy of Pathology) Congress (APIAP 2011)
  • Place of Presentation: Taipei International Convention Center (Taipei, Taiwan)(招待講演)
  • Year and Date: 2011-05-24