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非定型リピート翻訳を標的とした前頭側頭葉変性症に対する新規治療法の探索

Research Project

Project/Area Number 22KJ2148
Project/Area Number (Other) 22J12248 (2022)
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeMulti-year Fund (2023)
Single-year Grants (2022)
Section国内
Review Section Basic Section 52030:Psychiatry-related
Research InstitutionOsaka University

Principal Investigator

後藤 志帆  大阪大学, 医学系研究科, 特別研究員(DC2)

Project Period (FY) 2023-03-08 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2023: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2022: ¥900,000 (Direct Cost: ¥900,000)
Keywords前頭側頭葉変性症 / FTLD / ALS
Outline of Research at the Start

C9orf72遺伝子の非翻訳領域におけるGGGGCCリピート異常伸長変異は前頭側頭葉変性症(FTLD)と筋萎縮性側索硬化症(ALS)の共通の遺伝的原因の1つである。このリピート配列がRAN翻訳と呼ばれる非典型的な翻訳により、その毒性が病態に関与すると考えられているDPRタンパクに翻訳される。本研究ではRAN翻訳の詳細なメカニズムを明らかにすることでC9orf72遺伝子関連FTLD/ALSの新規治療法の開発を目指す。

Outline of Annual Research Achievements

本研究ではC9orf72遺伝子変異型の前頭側頭葉変性症(C9-FTLD)における非定型翻訳の詳細なメカニズムを解明することにより新規治療法を探索することを目的としてきた。C9-FTLDでは、当該遺伝子中にあるGGGGCCリピート配列が異常に伸長しており、この配列が転写されRAN翻訳(repeat-associated non-AUG translation)という非定型翻訳を受けることにより毒性DPRタンパク質が産生される。本研究では5種類あるDPRタンパク質のうちの1つpoly-GA(Glycine-Alanine)タンパク質の翻訳を調整する因子としてeIF5を同定した。細胞モデルを用いた検討では、eIF5の発現を低下させるとpoly-GAの発現量が低下し、eIF5を過剰発現するとpoly-GAは増加した。eIF5の過剰発現はRAN翻訳を促進するが通常の翻訳は増加させないことも明らかにした。さらに、リピートを発現させたショウジョウバエモデルにおけるeIF5の発現低下はpoly-GAの発現量を減少させた。以上の結果からeIF5はC9orf72遺伝子変異型の前頭側頭変性症の治療ターゲットとなる可能性があると考えている。
これまでに得た研究成果について国際誌Journal of Biological chemistryに報告し、第42回日本認知症学会とリスボンで開催されたADPD 2024での発表も行った。

Report

(2 results)
  • 2023 Annual Research Report
  • 2022 Annual Research Report
  • Research Products

    (27 results)

All 2024 2023 2022

All Journal Article (8 results) (of which Peer Reviewed: 8 results,  Open Access: 7 results) Presentation (19 results) (of which Int'l Joint Research: 9 results)

  • [Journal Article] PABPC1 mediates degradation of C9orf72-FTLD/ALS GGGGCC repeat RNA2024

    • Author(s)
      Uozumi Ryota、Mori Kohji、Gotoh Shiho、Miyamoto Tesshin、Kondo Shizuko、Yamashita Tomoko、Kawabe Yuya、Tagami Shinji、Akamine Shoshin、Ikeda Manabu
    • Journal Title

      iScience

      Volume: 27 Issue: 3 Pages: 109303-109303

    • DOI

      10.1016/j.isci.2024.109303

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS2024

    • Author(s)
      Gotoh Shiho、Mori Kohji、Fujino Yuzo、Kawabe Yuya、Yamashita Tomoko、Omi Tsubasa、Nagata Kenichi、Tagami Shinji、Nagai Yoshitaka、Ikeda Manabu
    • Journal Title

      Journal of Biological Chemistry

      Volume: 300 Issue: 3 Pages: 105703-105703

    • DOI

      10.1016/j.jbc.2024.105703

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] RNA Dysmetabolism and Repeat-Associated Non-AUG Translation in Frontotemporal Lobar Degeneration/Amyotrophic Lateral Sclerosis due to <i>C9orf72</i> Hexanucleotide Repeat Expansion2023

    • Author(s)
      Kohji Mori, Shiho Gotoh, Ryota Uozumi, Tesshin Miyamoto, Shoshin Akamine, Yuya Kawabe, Shinji Tagami, Manabu Ikeda
    • Journal Title

      JMA Journal

      Volume: 6 Issue: 1 Pages: 9-15

    • DOI

      10.31662/jmaj.2022-0160

    • ISSN
      2433-328X, 2433-3298
    • Year and Date
      2023-01-16
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characteristics of very late-onset schizophrenia-like psychosis classified with the biomarkers for Alzheimer’s disease: a retrospective cross-sectional study2023

    • Author(s)
      Satake Yuto、Kanemoto Hideki、Taomoto Daiki、Suehiro Takashi、Koizumi Fuyuki、Sato Shunsuke、Wada Tamiki、Matsunaga Keiko、Shimosegawa Eku、Gotoh Shiho、Mori Kohji、Morihara Takashi、Yoshiyama Kenji、Ikeda Manabu
    • Journal Title

      International Psychogeriatrics

      Volume: Jan 30 Issue: 1 Pages: 1-14

    • DOI

      10.1017/s1041610222001132

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cerebrospinal fluid amyloid beta with amyloid positron emission tomography concordance rates in a heterogeneous group of patients including late‐onset psychotic disorders: a retrospective cross‐sectional study2023

    • Author(s)
      Satake Yuto、Kanemoto Hideki、Gotoh Shiho、Akamine Shoshin、Suehiro Takashi、Matsunaga Keiko、Shimosegawa Eku、Yoshiyama Kenji、Morihara Takashi、Mori Kohji、Ikeda Manabu
    • Journal Title

      Psychogeriatrics

      Volume: 23 Issue: 6 Pages: 1091-1093

    • DOI

      10.1111/psyg.13024

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A heterozygous splicing variant IVS9-7A>T in intron 9 of the MAPT gene in a patient with right-temporal variant frontotemporal dementia with atypical 4 repeat tauopathy2023

    • Author(s)
      Mori Kohji、Shigenobu Kazue、Beck Goichi、Uozumi Ryota、Satake Yuto、Suzuki Maki、Kondo Shizuko、Gotoh Shiho、Yonenobu Yuki、Kawai Makiko、Suzuki Yuki、Saito Yuko、Morii Eiichi、Hasegawa Masato、Mochizuki Hideki、Murayama Shigeo、Ikeda Manabu
    • Journal Title

      Acta Neuropathologica Communications

      Volume: 11 Issue: 1 Pages: 130-130

    • DOI

      10.1186/s40478-023-01629-3

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aspects of degradation and translation of the expanded C9orf72 hexanucleotide repeat RNA2023

    • Author(s)
      Mori Kohji、Gotoh Shiho、Ikeda Manabu
    • Journal Title

      Journal of Neurochemistry

      Volume: 166 Issue: 2 Pages: 156-171

    • DOI

      10.1111/jnc.15847

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Plasma NfL is associated with mild cognitive decline in patients with diabetes2022

    • Author(s)
      Marutani N、Akamine S、Kanayama D、Gotoh S、Yanagida K、Maruyama R、Mori K、Miyamoto T、Adachi H、Sakagami Y、Yoshiyama K、Hotta M、Nagase A、Kozawa J、Maeda N、Otsuki M、Matsuoka T、Iwahashi H、Shimomura I、Murayama N、Watanabe H、Ikeda M、Mizuta I、Kudo T
    • Journal Title

      Psychogeriatrics

      Volume: - Issue: 3 Pages: 353-359

    • DOI

      10.1111/psyg.12819

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Presentation] eIF5 regulates poly-GA RAN translation in a cellular model of C9orf72 FTLD/ALS2024

    • Author(s)
      Shiho Gotoh, Kohji Mori, Tesshin Miyamoto, Ryota Uozumi, Tomoko Yamashita, Yuya Kawabe, Shoshin Akamine, Tsubasa Omi, Shizuko Kondo, Yoshitaka Nagai, Manabu Ikeda
    • Organizer
      ADPD 2024
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] KNOCKDOWN SCREENING FOR POTENTIAL RAN TRANSLATION MODULATORS IN CELLULAR MODELS OF C9ORF72 FTLD/ALS2024

    • Author(s)
      Kohji Mori, Shiho Gotoh, Ryota Uozumi, Tesshin Miyamoto, Shizuko Kondo, Yuya Kawabe, Shoshin Akamine, Yoshitaka Nagai, Manabu Ikeda
    • Organizer
      ADPD 2024
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Analysis of the GGC repeat length of the NOTCH2NLC gene responsible for Neuronal Intranuclear Inclusion Disease in a Japanese psychiatric dementia cohort2024

    • Author(s)
      Tesshin Miyamoto, Kohji Mori, Shoshin Akamine, Ryota Uozumi, Shiho Gotoh, Shizuko Kondo, Sumiyo Umeda, Yuto Satake, Takashi Suehiro, Hideki Kanemoto, Kenji Yoshiyama, Takashi Morihara, Manabu Ikeda
    • Organizer
      ADPD 2024
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] APEX2-BIOTINYLATION PROTEOMICS DISCOVERED THAT POLY (A)-BINDING PROTEIN MEDIATES THE DEGRADATION OF C9ORF72-GGGGCC REPEAT RNA.2024

    • Author(s)
      Ryota Uozumi, Kohji Mori, Shiho Gotoh, Tesshin Miyamoto, Shizuko Kondo, Tomoko Yamashita, Yuya Kawabe, Shinji Tagami, Shoshin Akamine, Manabu Ikeda
    • Organizer
      ADPD 2024
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 近接標識プロテオミクスによるC9orf72-GGGGCCリピートRNA分解タンパク質の同定2023

    • Author(s)
      魚住 亮太, 森 康治, 後藤 志帆, 宮本 哲愼, 近藤 志都子, 山下 智子, 河邉 有哉, 田上 真次, 赤嶺 祥真, 池田 学
    • Organizer
      日本認知症学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 阪大精神科認知症コホートにおけるNOTCH2NLC遺伝子GGCリピート長の解析2023

    • Author(s)
      宮本 哲愼, 森 康治, 魚住 亮太, 後藤 志帆, 近藤 志都子, 赤嶺 祥真, 佐竹 祐人, 佐藤 俊介, 鐘本 英輝, 吉山 顕次, 池田 学
    • Organizer
      日本認知症学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] C9orf72遺伝子変異FTDの治療法開発に向けたRAN翻訳調整因子の探索2023

    • Author(s)
      後藤 志帆, 森 康治, 宮本 哲愼, 魚住 亮太, 山下 智子, 赤嶺 祥真, 近江 翼, 近藤 志都子, 河邉 有哉, 永井 義隆, 池田 学
    • Organizer
      日本認知症学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Analysis of GGC repeat length of NOTCH2NLC gene in a cohort of dementia patients in the Department of Psychiatry, Osaka University Medical Hospital2023

    • Author(s)
      Tesshin Miyamoto, Kohji Mori, Ryota Uozumi, Shiho Gotoh, Shizuko Kondo, Sumiyo Umeda, Yuto Satake, Satoshi Suehiro, Syunsuke Satoh, Hideki Kanemoto, Kenji Yoshiyama, Shoshin Akamine, Takeshi Morihara, Manabu Ikeda
    • Organizer
      The 66th Annual Meeting of the Japanese Society for Neuro chemistry
    • Related Report
      2023 Annual Research Report
  • [Presentation] APEX2 proteomics revealed a molecular which promotes hnRNPA3-mediated C9orf72 repeat RNA degradation in FTLD/ALS.2023

    • Author(s)
      Ryota Uozumi, Kohji Mori, Shiho Gotoh, Tesshin Miyamoto, Shizuko Kondo, Tomoko Yamashita, Yuya Kawabe, Shoshin Akamine, Manabu Ikeda
    • Organizer
      The 66th Annual Meeting of the Japanese Society for Neuro chemistry
    • Related Report
      2023 Annual Research Report
  • [Presentation] SUPPRESSION OF A NOVEL RAN TRANSLATION REGULATOR REDUCES POLY-GADPR EXPRESSION IN A CELLULAR MODEL OF C9ORF72 FTLD/ALS.2023

    • Author(s)
      Shiho Gotoh
    • Organizer
      ADPD 2023
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] PROXIMITY LABELLING PROTEOMICS IDENTIFIED A NOVEL MOLECULE IN THE C9ORF72 REPEAT RNA DEGRADATION PATHWAY IN FTLD/ALS.2023

    • Author(s)
      Uozumi R., Mori K., Gotoh S. et al
    • Organizer
      ADPD 2023
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ARGININE-RICH DIPEPTIDE REPEAT PROTEINS INHIBIT THE ACTIVITY OF THE RNA EXOSOME COMPLEX AND PROMOTE THE ACCUMULATION OF C9ORF72 EXPANDED HEXANUCLEOTIDE REPEAT RNA2023

    • Author(s)
      Mori K., Kawabe Y., Yamashita T., Gotoh S. et al
    • Organizer
      ADPD 2023
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Functional analysis of a potential RAN translation regulator in C9orf72 FTLD/ALS2022

    • Author(s)
      Shiho Gotoh
    • Organizer
      ISFTD2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] C9orf72 FTLD/ALS関連RAN翻訳修飾因子の機能解析2022

    • Author(s)
      後藤志帆
    • Organizer
      第41回日 本認知症学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Coordination of RAN translation in FTLD/ALS causing C9orf72-GGGGCC repeat.2022

    • Author(s)
      後藤志帆
    • Organizer
      第65回日本神経化学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] siRNA-knockdown screening for potential RAN translation modulators in cellularmodels of C9orf72 FTLD/ALS2022

    • Author(s)
      Mori K, Gotoh S. et al
    • Organizer
      ISFTD2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] C9orf72-FTLD/ALSにおけるGGGGCC リピートRNA分解促進因子の同定2022

    • Author(s)
      魚住亮太, 森康治, 後藤志帆, 他
    • Organizer
      第41回日本認知症学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 精神科認知症コホートにおけるNOTCH2NLC遺伝子GGCリピート長の解析2022

    • Author(s)
      宮本 哲愼, 森 康治, 魚住 亮太, 後藤 志帆, 他
    • Organizer
      第41回日本認知症学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] アルツハイマー病バイオマーカー陽性のVLOSLPの特徴2022

    • Author(s)
      佐竹祐人、鐘本英輝、垰夲大喜、小泉冬木、末廣聖、佐藤俊介、和田民樹、吉山顕次、後藤志帆、他
    • Organizer
      第41回日本認知症学会
    • Related Report
      2022 Annual Research Report

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Published: 2022-04-28   Modified: 2024-12-25  

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