Investigation of ALS/FTLD pathogenesis based on translational deterioration due to ribosome dysfunction in axons

• Project/Area Number: 16K09690
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Osaka University
• Principal Investigator: NAGANO Seiichi 大阪大学, 医学系研究科, 准教授 (40362727)
• Co-Investigator(Kenkyū-buntansha): 永井 義隆 大阪大学, 医学系研究科, 寄附講座教授 (60335354)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: TDP-43 / 軸索輸送 / 筋萎縮性側索硬化症 / 前頭側頭葉変性症 / リボソーム蛋白質 / 局所翻訳 / mRNA / リボソーム蛋白質mRNA

Outline of Final Research Achievements

In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), abnormal deposition of the RNA-binding protein TDP-43 in neurons was observed, suggesting a relationship with the pathogenesis. We hypothesized that impairment of TDP-43-mediated mRNA transport to neuronal axons would cause ALS/FTLD, and identified ribosomal protein (Rp) mRNA as its target. It was suggested that Rp mRNA is transported by binding and colocalizing with TDP-43 in axons, and the transported Rp mRNA is locally translated in axons and assembled into endogenous ribosomes. In the axons in which TDP-43 was down-regulated, local translational ability by ribosomes and axonal outgrowth was impaired, while the disturbance was ameliorated by overexpression of each Rp.

Academic Significance and Societal Importance of the Research Achievements

筋萎縮性側索硬化症（ALS）、前頭側頭葉変性症（FTLD）は根本的治療法のない重篤な神経変性疾患であり、一刻も早い効果的治療法の開発が切望されている。ALS/FTLDではRNA結合蛋白質TDP-43の神経細胞での局在異常が知られているが、我々は独自に開発した神経細胞区画培養法を用いて神経軸索を選択的に解析する手法を確立し、それによりTDP-43による軸索輸送標的としてリボソーム蛋白質（Rp）mRNAを同定した。Rp mRNAの発現を増加させる薬剤により、ALS/FTLDの新たな治療法が開発されることが期待される。

Research Products

• [Journal Article] Characteristic Features of FUS Inclusions in Spinal Motor Neurons of Sporadic Amyotrophic Lateral Sclerosis. (2020)
  • Author(s): Ikenaka K, Ishigaki S, Iguchi Y, Kawai K, Fujioka Y, Yokoi S, Abdelhamid RF, Nagano S, Mochizuki H, Katsuno M, Sobue G.
  • Journal Title: J Neuropathol Exp Neurol Volume: 79 Issue: 4 Pages: 370-377
  • DOI: 10.1093/jnen/nlaa003
  • Peer Reviewed
• [Journal Article] Structurally Distinct α‐Synuclein Fibrils Induce Robust Parkinsonian Pathology (2019)
  • Author(s): Hayakawa Hideki、Nakatani Rie、Ikenaka Kensuke、Aguirre Cesar、Choong Chi‐Jing、Tsuda Hiroshi、Nagano Seiichi、Koike Masato、Ikeuchi Takeshi、Hasegawa Masato、Papa Stella M.、Nagai Yoshitaka、Mochizuki Hideki、Baba Kousuke
  • Journal Title: Movement Disorders Volume: 35 Issue: 2 Pages: 256-267
  • DOI: 10.1002/mds.27887
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A clinicopathological study of ALS with L126S mutation in the SOD1 gene presenting with isolated inferior olivary hypertrophy (2019)
  • Author(s): Hideshima Makoto、Beck Goichi、Yamadera Misaki、Motoyama Yuichi、Ikenaka Kensuke、Kakuda Keita、Tsuda Hiroshi、Nagano Seiichi、Fujimura Harutoshi、Morii Eiichi、Murayama Shigeo、Mochizuki Hideki
  • Journal Title: Neuropathology Volume: Epub Issue: 2 Pages: 191-195
  • DOI: 10.1111/neup.12620
  • Peer Reviewed
• [Journal Article] Critical role of CRAG, a splicing variant of centaurin-γ3/AGAP3, in ELK1-dependent SRF activation at PML bodies. (2019)
  • Author(s): Nagashima S, Takeda K, Shiiba I, Higashi M, Fukuda T, Tokuyama T, Matsushita N, Nagano S, Araki T, Kaneko M, Shioi G, Inatome R, Yanagi S.
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 20107-20107
  • DOI: 10.1038/s41598-019-56559-9
  • Peer Reviewed / Open Access
• [Journal Article] Altered immunoreactivity of ErbB4, a causative gene product for ALS19, in the spinal cord of patients with sporadic ALS (2019)
  • Author(s): Takahashi Yuji、Uchino Akiko、Shioya Ayako、Sano Terunori、Matsumoto Chihiro、Numata‐Uematsu Yurika、Nagano Seiichi、Araki Toshiyuki、Murayama Shigeo、Saito Yuko
  • Journal Title: Neuropathology Volume: 39 Issue: 4 Pages: 268-278
  • DOI: 10.1111/neup.12558
  • Peer Reviewed / Open Access
• [Journal Article] 筋萎縮性側索硬化症とRNA代謝異常． (2019)
  • Author(s): 長野清一，望月秀樹．
  • Journal Title: 日本医事新報 Volume: 4964 Pages: 48-48
• [Journal Article] 筋萎縮性側索硬化症に対する肝細胞増殖因子を用いた治験． (2019)
  • Author(s): 長野清一，割田 仁，望月秀樹，青木正志．
  • Journal Title: 神経治療学 Volume: 36 Pages: 462-464
  • NAID: 130007834999
  • Peer Reviewed
• [Journal Article] Inhibition of collapsin response mediator protein-2 phosphorylation ameliorates motor phenotype of ALS model mice expressing SOD1G93A. (2019)
  • Author(s): 3. Numata-Uematsu Y, Wakatsuki S, Nagano S, Shibata M, Sakai K, Ichinohe N, Mikoshiba K, Ohshima T, Yamashita N, Goshima Y, Araki T.
  • Journal Title: Neurosci Res Volume: 139 Pages: 63-68
  • DOI: 10.1016/j.neures.2018.08.016
  • Peer Reviewed
• [Journal Article] Ultrasonication-based rapid amplification of α-synuclein aggregates in cerebrospinal fluid. (2019)
  • Author(s): 2. Kakuda K, Ikenaka K, Araki K, So M, Aguirre C, Kajiyama Y, Konaka K, Noi K, Baba K, Tsuda H, Nagano S, Ohmichi T, Nagai Y, Tokuda T, El-Agnaf O, Ogi H, Goto Y, Mochizuki H.
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 6001-6001
  • DOI: 10.1038/s41598-019-42399-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 筋萎縮性側索硬化症とRNA代謝異常 (2018)
  • Author(s): 長野清一、望月秀樹
  • Journal Title: 日本医事新報 Volume: in press
• [Journal Article] 大脳皮質基底核変性症―歴史と概要． (2017)
  • Author(s): 長野清一，望月秀樹．
  • Journal Title: Clinical Neuroscience Volume: 35 Pages: 302-303
• [Journal Article] Transgenic monkey model of the polyglutamine diseases recapitulating progressive neurological symptoms. (2017)
  • Author(s): Tomioka I, Ishibashi H, Minakawa EN, Motohashi HH, Takayama O, Saito Y, Popiel HA, Puentes S, Owari K, Nakatani T, Nogami N, Yamamoto K, Noguchi S, Yonekawa T, Tanaka Y, Fujita N, Suzuki H, Kikuchi H, Aizawa S, Nagano S, Yamada D, Nishino I, Ichinohe N, Wada K, Kohsaka S, Nagai Y, Seki K.
  • Journal Title: eNeuro Volume: 4 Issue: 2 Pages: 0250-56
  • DOI: 10.1523/eneuro.0250-16.2017
  • NAID: 120007100051
  • Peer Reviewed / Open Access
• [Presentation] TDP-43 controls ribosomal RNA maturation by regulating the function of ribosomal proteins. (2019)
  • Author(s): Nagano S, Jinno J, Mochizuki H, Araki T.
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] 鉄と神経変性疾患―筋萎縮性側索硬化症（ALS）を中心に―． (2019)
  • Author(s): 長野清一．
  • Organizer: 第43回日本鉄バイオサイエンス学会学術集会
  • Invited
• [Presentation] TDP-43により軸索輸送される標的mRNAの探索． (2019)
  • Author(s): 長野清一．
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Presentation] リボソームの機能促進による筋萎縮性側索硬化症の新規治療戦略. (2019)
  • Author(s): 長野清一、望月秀樹．
  • Organizer: 大阪大学先導的学際研究機構シンポジウム「未来医療を推進する革新的技術のフロンティア」
• [Presentation] Identification of target mRNA transported to axons by TDP-43. (2019)
  • Author(s): Nagano S, Ueyama M, Nagai Y, Mochizuki H, Araki T.
  • Organizer: 第15回成体脳ニューロン新生懇談会
• [Presentation] Regulation of TDP-43-mediated neurotoxicity by ribosome-related factors. (2018)
  • Author(s): Nagano S, Mochizuki H, Araki T.
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] Gene therapy for ALS. (2018)
  • Author(s): Nagano S.
  • Organizer: 第24回日本遺伝子細胞治療学会学術集会
  • Invited
• [Presentation] Identification of target mRNA transported to axons by TDP-43. (2018)
  • Author(s): Nagano S, Ueyama M, Nagai Y, Mochizuki H, Araki T.
  • Organizer: 143rd Annual Meeting of the American Neurological Association
  • Int'l Joint Research
• [Presentation] Regulation of TDP-43-mediated neurotoxicity by ribosome-related factors. (2018)
  • Author(s): Nagano S, Mochizuki H, Araki T.
  • Organizer: 5th RNA Metabolism in Neurological Disease Conference
  • Int'l Joint Research
• [Presentation] ALSにおけるHGF治験． (2018)
  • Author(s): 長野清一、割田 仁、望月秀樹、青木正志．
  • Organizer: 第36回日本神経治療学会学術集会
  • Invited
• [Presentation] Identification of target mRNA transported to axons by TDP-43 (2017)
  • Author(s): S. Nagano, M. Ueyama, Y. Nagai, H. Mochizuki, T. Araki
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] リボソーム関連因子によるTDP-43神経毒性の制御 (2017)
  • Author(s): 長野清一、望月秀樹、荒木敏之
  • Organizer: 第36回日本認知症学会学術集会
• [Presentation] 筋萎縮性側索硬化症（ALS）の病態解明と治療薬開発に向けて-Review メタルバイオの視点から－ (2017)
  • Author(s): 長野清一
  • Organizer: メタルバイオサイエンス研究会2017
  • Invited
• [Presentation] Identification of target mRNA transported to axons by TDP-43 (2017)
  • Author(s): S. Nagano, M. Ueyama, Y. Nagai, H. Mochizuki, T. Araki
  • Organizer: 28th International Symposium on ALS/MND
  • Int'l Joint Research
• [Presentation] Neurotoxicity of TDP-43 is linked to axonal dysfunction of ribosomal proteins (2016)
  • Author(s): Nagano S, Ueyama M, Wada K, Nagai Y, Araki T.
  • Organizer: 第35回日本認知症学会学術集会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2016-12-01
• [Presentation] TDP-43によるリボソーム蛋白質mRNAの神経軸索への輸送 (2016)
  • Author(s): 長野清一，荒木敏之．
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] Identification of target mRNA transported to axons by TDP-43 (2016)
  • Author(s): Nagano S, Ueyama M, Wada K, Nagai Y, Araki T.
  • Organizer: 11th Brain Research Conference
  • Place of Presentation: Paradise Point, San Diego, USA
  • Year and Date: 2016-11-10
  • Int'l Joint Research
• [Presentation] Neuronal toxicity of TDP-43 is associated with the dysfunction of ribosomal proteins in axons (2016)
  • Author(s): Nagano S, Ueyama M, Wada K, Nagai Y, Saito Y, Araki T.
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター、神戸ポートピアホテル
  • Year and Date: 2016-05-18
• [Book] 今日の治療指針 (2020)
  • Author(s): 長野清一，望月秀樹．
  • Total Pages: 2192
  • Publisher: 医学書院
  • ISBN: 9784260039390
• [Book] 神経変性疾患ハンドブック (2018)
  • Author(s): 長野清一，望月秀樹．
  • Total Pages: 406
  • Publisher: 南江堂
  • ISBN: 9784524256174
• [Book] Annual Review 神経 2018 (2018)
  • Author(s): 長野清一、望月秀樹
  • Total Pages: 344
  • Publisher: 中外医学社
• [Book] Update on amyotrophic lateral sclerosis (2016)
  • Author(s): Nagano S, Araki T.
  • Total Pages: 278
  • Publisher: InTech Publisher
• [Book] 実験医学別冊「マウス表現型解析スタンダード」 (2016)
  • Author(s): 長野清一，金井雅裕，永井義隆．
  • Total Pages: 351
  • Publisher: 羊土社
• [Remarks] 研究室ホームページ
  • URL: http://www.med.osaka-u.ac.jp/pub/neurol/myweb6/Top.html
• [Patent(Industrial Property Rights)] 筋萎縮性側索硬化症を含む神経疾患の予防剤及び／又は治療剤 (2018)
  • Inventor(s): 望月秀樹、長野清一、佐々木勉、鐘其静、岡田尚巳、平井幸彦
  • Industrial Property Rights Holder: 望月秀樹、長野清一、佐々木勉、鐘其静、岡田尚巳、平井幸彦
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-141692
  • Filing Date: 2018
• [Patent(Industrial Property Rights)] TDP-43プロテイノパチー治療用組成物 (2016)
  • Inventor(s): 長野清一、荒木敏之、上山盛夫、永井義隆
  • Industrial Property Rights Holder: 長野清一、荒木敏之、上山盛夫、永井義隆
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-087320
  • Filing Date: 2016-04-25