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The function of G-quadruplexes in learning and memory and its pharmaceutical research

Research Project

Project/Area Number 20H03393
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 47040:Pharmacology-related
Research InstitutionKumamoto University

Principal Investigator

Shioda Norifumi  熊本大学, 発生医学研究所, 教授 (00374950)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2021: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2020: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
Keywordsグアニン四重鎖 / RNA高次構造 / 神経機能 / mRNA / ストレス顆粒 / 脳機能 / 認知障害 / DNA可塑性 / 学習・記憶 / DNA 可塑性 / RNA エングラム
Outline of Research at the Start

本研究では、 「グアニン四重鎖 (G-quadruplex; G4) 構造」の学習・記憶における役割を明らかにするため、G4 構造と神経可塑性・記憶痕跡(エングラム)との関与を解析し、 「DNA 可塑性」と「RNA エングラム」の存在を証明する。つまり、G4 構造が脳機能における学習・記憶の分子実態のひとつであることを生物学的・及び薬理学的に明らかにする。この成果は、特殊核酸 G4 構造を認知症などの脳機能異常疾患におけるアンメット・メディカル・ニーズの新たな治療薬の標的として社会に提示できる。

Outline of Final Research Achievements

G-quadruplex (G4) is a unique nucleic acid structure formed when a four-stranded structure is produced within a single-stranded guanine-rich sequence. Four guanine molecules form a square planar arrangement, termed G-quartet, which are stacked on top of each other to form the G4 structure in DNA (G4DNA) and in RNA (G4RNA). Recent studies have revealed that G4DNA and G4RNA are folded in cells, which suggested their biological and pharmacological significance in DNA replication, transcription, and RNA metabolism. So far, we have reported the following; 1) G4 is a target of cognitive function therapy for ATR-X intellectual disability syndrome, in which mutations are found in a G4 binding protein ATRX. 2) G4 is formed in heterochromatin depending on neuronal development. Here, we found that G4 promotes prionoids in a CGG triplet repeat disease, FXTAS. In addition, 5-aminolevulinic acid is a potential candidate drug for treating some neurological diseases through the G4 binding ability.

Academic Significance and Societal Importance of the Research Achievements

近年、アルツハイマー病等の神経変性疾患の発症にプリオノイド機構が関与することが注目されているが、その細胞内メカニズムは未解明である。本研究から、プリオノイドの引き金が G4 構造の凝集であると考えられた。現在、タウやαシヌクレインの凝集と G4 構造の関与を解析中である。また、 FXTAS と同様の神経症状を呈するグアニンリッチ・リピートに由来する疾患がロングリード・シーケンス技術により多数発見されている。本研究で使用した G4 構造作用薬5-アミノレブリン酸は、安全性の高い既承認医薬品である。従って、本研究により発見されたプリオノイド機構を基盤とした神経変性疾患全般に対する治療が期待される。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (23 results)

All 2023 2022 2021 2020

All Journal Article (15 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 15 results,  Open Access: 10 results) Presentation (7 results) (of which Int'l Joint Research: 2 results,  Invited: 5 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] RNA G-quadruplex organizes stress granule assembly through DNAPTP6 in neurons2023

    • Author(s)
      Asamitsu Sefan、Yabuki Yasushi、Matsuo Kazuya、Kawasaki Moe、Hirose Yuki、Kashiwazaki Gengo、Chandran Anandhakumar、Bando Toshikazu、Wang Dan Ohtan、Sugiyama Hiroshi、Shioda Norifumi
    • Journal Title

      Science Advances

      Volume: 9 Issue: 8

    • DOI

      10.1126/sciadv.ade2035

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] α‐Synuclein decoy peptide protects mice against α‐synuclein‐induced memory loss2023

    • Author(s)
      Guo Qingyun、Kawahata Ichiro、Jia Wenbin、Wang Haoyang、Cheng An、Yabuki Yasushi、Shioda Norifumi、Fukunaga Kohji
    • Journal Title

      CNS Neuroscience & Therapeutics

      Volume: Online ahead of print. Issue: 6 Pages: 1-14

    • DOI

      10.1111/cns.14120

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Small molecule-based detection of non-canonical RNA G-quadruplex structures that modulate protein translation2022

    • Author(s)
      Yousuke Katsuda, Shin-ichi Sato, Maimi Inoue, Hisashi Tsugawa, Takuto Kamura, Tomoki Kida, Rio Matsumoto, Sefan Asamitsu, Norifumi Shioda, Shuhei Shiroto, Yoshiki Oosawatsu, Kenji Yatsuzuka, Yusuke Kitamura, Masaki Hagihara, Toshihiro Ihara and Motonari Uesugi
    • Journal Title

      Nucleic Acids Research

      Volume: 50 Issue: 14 Pages: 8143-8153

    • DOI

      10.1093/nar/gkac580

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 5-Aminolevulinic acid antiviral efficacy against SARS-CoV-2 omicron variant in vitro2022

    • Author(s)
      Ngwe Tun Mya Myat、Sakura Takaya、Sakurai Yasuteru、Kurosaki Yohei、Inaoka Daniel Ken、Shioda Norifumi、Smith Chris、Yasuda Jiro、Morita Kouichi、Kita Kiyoshi
    • Journal Title

      Tropical Medicine and Health

      Volume: 50 Issue: 1 Pages: 6-6

    • DOI

      10.1186/s41182-022-00422-7

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Antiviral activity of 5-aminolevulinic acid against variants of severe acute respiratory syndrome coronavirus 22022

    • Author(s)
      Ngwe Tun Mya Myat、Sakura Takaya、Sakurai Yasuteru、Kurosaki Yohei、Inaoka Daniel Ken、Shioda Norifumi、Yasuda Jiro、Kita Kiyoshi、Morita Kouichi
    • Journal Title

      Tropical Medicine and Health

      Volume: 50 Issue: 1 Pages: 6-6

    • DOI

      10.1186/s41182-021-00397-x

    • NAID

      120007190850

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Father-to-offspring transmission of extremely long NOTCH2NLC repeat expansions with contractions: genetic and epigenetic profiling with long-read sequencing2021

    • Author(s)
      Fukuda H, Yamaguchi D, Nyquist K, Yabuki Y, Miyatake S, Uchiyama Y, Hamanaka K, Saida K, Koshimizu E, Tsuchida N, Fujita A, Mitsuhashi S, Ohbo K, Satake Y, Sone J, Doi H, Morihara K, Okamoto T, Takahashi Y, Wenger AM, Shioda N, Tanaka F, Matsumoto N, Mizuguchi T
    • Journal Title

      Clin Epigenetics

      Volume: 13 Issue: 1 Pages: 204-204

    • DOI

      10.1186/s13148-021-01192-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Potential roles of G-quadruplex structures in RNA granules for physiological and pathological phase separation2021

    • Author(s)
      Asamitsu Sefan、Shioda Norifumi
    • Journal Title

      The Journal of Biochemistry

      Volume: mvab018 Issue: 5 Pages: 527-533

    • DOI

      10.1093/jb/mvab018

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome2021

    • Author(s)
      Asamitsu Sefan、Yabuki Yasushi、Ikenoshita Susumu、Kawakubo Kosuke、Kawasaki Moe、Usuki Shingo、Nakayama Yuji、Adachi Kaori、Kugoh Hiroyuki、Ishii Kazuhiro、Matsuura Tohru、Nanba Eiji、Sugiyama Hiroshi、Fukunaga Kohji、Shioda Norifumi
    • Journal Title

      Science Advances

      Volume: 7 Issue: 3

    • DOI

      10.1126/sciadv.abd9440

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cav3.1 t‐type calcium channel is critical for cell proliferation and survival in newly generated cells of the adult hippocampus2021

    • Author(s)
      Yabuki Yasushi、Matsuo Kazuya、Yu Mengze、Xu Jing、Sakimura Kenji、Shioda Norifumi、Fukunaga Kohji
    • Journal Title

      Acta Physiologica

      Volume: e13613 Issue: 1

    • DOI

      10.1111/apha.13613

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Establishment of FXS-A9 panel with a single human X chromosome from fragile X syndrome-associated individual2021

    • Author(s)
      Nakayama Yuji、Adachi Kaori、Shioda Nofirifumi、Maeta Shoya、Nanba Eiji、Kugoh Hiroyuki
    • Journal Title

      Experimental Cell Research

      Volume: 398 Issue: 2 Pages: 112419-112419

    • DOI

      10.1016/j.yexcr.2020.112419

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A newly identified NES sequence present in spastin regulates its subcellular localization and microtubule severing activity2021

    • Author(s)
      Sakoe Kumi、Shioda Norifumi、Matsuura Tohru
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

      Volume: 1868 Issue: 1 Pages: 118862-118862

    • DOI

      10.1016/j.bbamcr.2020.118862

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Anti-Epileptic Effects of FABP3 Ligand MF1 through the Benzodiazepine Recognition Site of the GABAA Receptor2020

    • Author(s)
      Yabuki Yasushi、Liu Jiaqi、Kawahata Ichiro、Izumi Hisanao、Shinoda Yasuharu、Koga Kohei、Ueno Shinya、Shioda Norifumi、Fukunaga Kohji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 15 Pages: 5525-5525

    • DOI

      10.3390/ijms21155525

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fatty acid binding protein 3 enhances the spreading and toxicity of a-synuclein in mouse brain.2020

    • Author(s)
      Yabuki Y, Matsuo K, Kawahata I, Fukui N, Mizobata T, Kawata Y, Owada Y, Shioda N, Fukunaga K.
    • Journal Title

      Int J Mol Sci

      Volume: - Issue: 6 Pages: 2230-2230

    • DOI

      10.3390/ijms21062230

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification and immunohistochemical characterization of G-quadruplexes in mouse brain.2020

    • Author(s)
      Asamitsu S, Imai Y, Yabuki Y, Ikenoshita S, Takeuchi M, Kashiwagi H, Tanoue Y, Fukuda T, Shioda N.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: in press Issue: 1 Pages: 67-74

    • DOI

      10.1016/j.bbrc.2020.01.145

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pharmacological prospects of G-quadruplexes for neurological diseases using porphyrins.2020

    • Author(s)
      Asamitsu S, Yabuki Y, Ikenoshita S, Wada T, Shioda N.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: - Issue: 1 Pages: 51-55

    • DOI

      10.1016/j.bbrc.2020.01.054

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Presentation] Pathophysiological significance of G-quadruplexes in neurobiology2023

    • Author(s)
      Norifumi Shioda
    • Organizer
      G4 webiner
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 神経疾患におけるグアニン四重鎖の細胞内機能2022

    • Author(s)
      塩田倫史
    • Organizer
      NEURO2022
    • Related Report
      2022 Annual Research Report
  • [Presentation] グアニン四重鎖の神経生物学的機能の解明を目指して2022

    • Author(s)
      塩田倫史
    • Organizer
      2022年度 若手支援技術講習会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 神経疾患の新しい治療標的 ~グアニン四重鎖~2021

    • Author(s)
      塩田倫史
    • Organizer
      第44回日本神経科学大会・CJK第1回国際会議
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 神経生物学におけるDNA・RNA 高次構造の機能解明を目指して.2021

    • Author(s)
      塩田倫史
    • Organizer
      日本ケミカルバイオロジー学会第15回年会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 脳神経におけるDNA・RNA 高次構造の機能解明2021

    • Author(s)
      塩田 倫史
    • Organizer
      三融会・武田神経科学シンポジウム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 脳神経におけるグアニン四重鎖の機能解明を目指して2020

    • Author(s)
      塩田 倫史
    • Organizer
      Chem for研究会(Chemistry for Complex Processes in Cells)
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Patent(Industrial Property Rights)] リピート結合剤2020

    • Inventor(s)
      杉山弘、坂東俊和、池田修司、塩田倫史、矢吹悌、朝光世煌
    • Industrial Property Rights Holder
      杉山弘、坂東俊和、池田修司、塩田倫史、矢吹悌、朝光世煌
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-110752
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2024-01-30  

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