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Role of stress-induced transcription factor ATF3 on neurodegeneration of prion diseases

Research Project

Project/Area Number 19H03119
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 42020:Veterinary medical science-related
Research InstitutionHokkaido University

Principal Investigator

HORIUCHI MOTOHIRO  北海道大学, 獣医学研究院, 教授 (30219216)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2021: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2020: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
Keywordsプリオン / ATF3 / 神経細胞死 / フェロトーシス / プリオン病 / 神経変性疾患 / ストレス応答 / AFT3 / 小胞体ストレス / アデノ随伴ウイルスベクター / 神経細胞 / CRISPR/Cas9
Outline of Research at the Start

プリオン病、アルツハイマー病など、タンパク質の異常凝集を伴う難治性の神経変性疾患では、小胞体ストレス、酸化ストレスなどに対するストレス応答が生じ、最終的には細胞機能が破綻して神経細胞死が生じる。神経細胞で生じる一連のストレス応答が明らかになれば、ストレス応答の制御による神経保護を標的とした治療法開発の道が開ける。研究代表者のグループは、プリオン感染マウスの視床の神経細胞で、ストレス誘導性の転写調節因子ATF3の発現が誘導され、神経細胞が脱落することを見出した。この現象を掘り下げ、プリオン病における神経変性機構の核心に迫る。

Outline of Final Research Achievements

In this study, we analyzed the role of stress-inducible activating transcription factor 3 (ATF3) in the pathobiology of prion diseases. ATF3-positive cells were significantly increased in the thalamus and pontine nucleus of prion-infected mice, where neuronal cell death is well-observed, and around 80% of ATF-3 positive cells were identified as neurons. Apoptosis were not observed in the thalamus, where pronounced neuronal cell death occurred. The amount of GPx4 in the thalamus tended to decrease with prion infection. The 4-HNE, a marker of lipid peroxidation, was less accumulated in ATF3-positive neurons than ATF3-negative neurons. These results suggested that neurons in the thalamus die of ferroptosis and that induction of ATF3 expression may mitigate lipid peroxidation in the neurons and suppress ferroptosis.

Academic Significance and Societal Importance of the Research Achievements

難治性神経変性疾患の一つであるプリオン病における神経細胞死に、脂質の過酸化が誘因となるフェロトーシスが関与する可能性を世界で初めて見いだしたことは、学術的に大きな意義がある。また、フェロトーシスの抑制が神経細胞死の抑制につながる可能性があり、治療法開発戦略の新たな治療標的となる点でも社会的な意義も大きいと考えられる。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (25 results)

All 2022 2021 2020 2019 Other

All Int'l Joint Research (1 results) Journal Article (13 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 13 results,  Open Access: 9 results) Presentation (10 results) (of which Int'l Joint Research: 5 results,  Invited: 1 results) Funded Workshop (1 results)

  • [Int'l Joint Research] コロラド州立大学(米国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Extended application of the rapid post‐mortem test kit for bovine spongiform encephalopathy to chronic wasting disease2022

    • Author(s)
      Matsuura Yuichi、Miyazawa Kohtaro、Horiuchi Motohiro、Suzuki Akio、Yokoyama Mayumi、Imamura Morikazu、Ikeda Keigo、Iwamaru Yoshifumi
    • Journal Title

      Microbiology and Immunology

      Volume: - Issue: 5 Pages: 212-215

    • DOI

      10.1111/1348-0421.12968

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Monitoring of chronic wasting disease using real-time quaking-induced conversion assay in Japan2021

    • Author(s)
      SUZUKI Akio、SAWADA Kazuhei、ERDENEBAT Temuulen、YAMASAKI Takeshi、TOBIUME Minoru、SUGA Kinuyo、HORIUCHI Motohiro
    • Journal Title

      Journal of Veterinary Medical Science

      Volume: 83 Issue: 11 Pages: 1735-1739

    • DOI

      10.1292/jvms.21-0368

    • NAID

      130008116910

    • ISSN
      0916-7250, 1347-7439
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Isolation of Human Lineage, Fluoroquinolone-Resistant and Extended-β-Lactamase-Producing Escherichia coli Isolates from Companion Animals in Japan2021

    • Author(s)
      Sato Toyotaka、Yokota Shin-ichi、Tachibana Tooru、Tamai Satoshi、Maetani Shigeki、Tamura Yutaka、Horiuchi Motohiro
    • Journal Title

      Antibiotics

      Volume: 10 Issue: 12 Pages: 1463-1463

    • DOI

      10.3390/antibiotics10121463

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Relationship between lactational performance and metabolic parameters of Mongolian native grazing mares2021

    • Author(s)
      SANDAGDORJ Badrakh、BAIGALMAA Tserenpil、BURENJARGAL Sedhuu、HORIUCHI Motohiro、ENKHDALAI Munkhbat、BAYANBAT Davaakhuu、JANCHIV Dashdorj、JAMYANDORJ Ooyo、ULZII-ORSHIKH Purevdorj、NYAM-OSOR Purevdorj
    • Journal Title

      Journal of Equine Science

      Volume: 32 Issue: 3 Pages: 91-98

    • DOI

      10.1294/jes.32.91

    • NAID

      130008086318

    • ISSN
      1340-3516, 1347-7501
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Refeeding activates neurons in the dorsomedial hypothalamus to inhibit food intake and promote positive valence2021

    • Author(s)
      Daigo Imoto, Izumi Yamamoto, Hirokazu Matsunaga, Toya Yonekura, Ming-Liang Lee, Kan X Kato, Takeshi Yamasaki, Shucheng Xu, Taiga Ishimoto, Satoshi Yamagata, Ken-Ichi Otsuguro, Motohiro Horiuchi , Norifumi Iijima, Kazuhiro Kimura, Chitoku Toda
    • Journal Title

      Molecular Metabiolism

      Volume: 54 Pages: 101366-101366

    • DOI

      10.1016/j.molmet.2021.101366

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Research Note: Antimicrobial resistance of Campylobacter species isolated from chickens near Ulaanbaatar city, Mongolia2021

    • Author(s)
      Byambajav Zolzaya、Bulgan Erdenebat、Hirai Yuji、Nakayama Momoko、Tanaka Misaki、Nitta Yurika、Suzuki Akio、Umemura Takashi、Altankhuu Bold、Tsagaan Alimaa、Vanaabaatar Batbaatar、Janchivdorj Erdenebaatar、Purevdorj Nyam-Osor、Ayushjav Narantuya、Yamasaki Takeshi、Horiuchi Motohiro
    • Journal Title

      Poultry Science

      Volume: 100 Issue: 3 Pages: 100916-100916

    • DOI

      10.1016/j.psj.2020.11.079

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Enhanced phosphorylation of PERK in primary cultured neurons as an autonomous neuronal response to prion infection2020

    • Author(s)
      Tanaka Misaki、Yamasaki Takeshi、Hasebe Rie、Suzuki Akio、Horiuchi Motohiro
    • Journal Title

      PLOS ONE

      Volume: 15 Issue: 6 Pages: e0234147-e0234147

    • DOI

      10.1371/journal.pone.0234147

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Involvement of N- and C-terminal region of recombinant cervid prion protein in its reactivity to CWD and atypical BSE prions in real-time quaking-induced conversion reaction in the presence of high concentrations of tissue homogenates2020

    • Author(s)
      Suzuki Akio、Sawada Kazuhei、Yamasaki Takeshi、Denkers Nathaniel D、Mathiason Candace K、Hoover Edward A、Horiuchi Motohiro
    • Journal Title

      Prion

      Volume: 14 Issue: 1 Pages: 283-295

    • DOI

      10.1080/19336896.2020.1858694

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Selective neuronal vulnerability is involved in cerebellar lesions of Guinea pigs infected with bovine spongiform encephalopathy (BSE) prions: Immunohistochemical and electron microscopic investigations2020

    • Author(s)
      Sakaguchi S, Shintani S, Kamio K, Sekiya A, Kato S, Muroi Y, Horiuchi M, Furuoka H.
    • Journal Title

      Neuropathology

      Volume: 40 Issue: 2 Pages: 167-179

    • DOI

      10.1111/neup.12613

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Enhancement of binding avidity by divalent binding is a key mechanism for abnormal isoform of prion protein-specific detection by anti-PrP monoclonal antibody 1322019

    • Author(s)
      Suzuki A, Yamasaki T, Hasebe R, Horiuchi M
    • Journal Title

      PLoS One

      Volume: 14 Issue: 6 Pages: e0217944-e0217944

    • DOI

      10.1371/journal.pone.0217944

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Tracking and clarifying differential traits of the classical- and atypical L-type bovine spongiform encephalopathy prions after transmission from cattle to cynomolgus monkeys2019

    • Author(s)
      Hagiwara, K., Yuko Sato, Y., Yamakawa, Y., Hara, H., Tobiume, M., Okemoto-Nakamura, Y., Sata, T., Horiuchi, M., Shibata, H., Ono, F.
    • Journal Title

      PLoS One

      Volume: 14

    • NAID

      120006812014

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Estimation of prion infectivity in tissues of cattle infected with atypical BSE by real time-quaking induced conversion assay2019

    • Author(s)
      Sawada K, Suzuki A, Yamasaki T, Iwamaru Y, Matsuura Y, Miyazawa K, Masujin K, Atarashi R, Horiuchi M
    • Journal Title

      Journal of Veterinary Medical Science

      Volume: 81 Issue: 6 Pages: 846-850

    • DOI

      10.1292/jvms.19-0003

    • NAID

      130007660450

    • ISSN
      0916-7250, 1347-7439
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The first isolation and identification of canine parvovirus (CPV) type 2c variants during 2016 - 2018 genetic surveillance of dogs in Mongolia.2019

    • Author(s)
      Uyangaa Temuujin, Ariunaa Tserendorj, Jumpei Fujiki, Yoshihiro Sakoda, Erdene-Ochir Tseren-Ochir, Masatoshi Okamatsu, Keita Matsuno, Tumenjargal Sharav, Motohiro Horiuchi, Takashi Umemura, Tungalag Chultemdorj.
    • Journal Title

      Infect. Genet. Evol.

      Volume: 73 Pages: 936-942

    • DOI

      10.1016/j.meegid.2019.05.006

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] プリオン22L株のグルタミン酸作動性神経細胞における易増殖性2021

    • Author(s)
      上森 望未、田中 美咲、Temuulen ERDENEBAT, 小松 勇介、鈴木 章夫、堀内 基広
    • Organizer
      第164回日本獣医学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] プリオン感染動物で見られるシナプス脱落についての比較病理学的検討2021

    • Author(s)
      星加 恭、能瀬 絵菜、小松 勇介、堀内 基広、古岡 秀文
    • Organizer
      第164回日本獣医学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Monitoring of chronic wasting disease using real-time quaking conversion assay in Japan2021

    • Author(s)
      Suzuki A, Sawada K, Erdenebat T, Yamasaki T, Tobiume M, Suga, K Horiuchi M
    • Organizer
      14th Asian Society of Conservation Medicine
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] GABA-negative neuron-prone propagation of prion 22L strain2021

    • Author(s)
      Erndenebat T, Uwamori N, Tanaka M, Komatsu Y, Suzuki A, Yamasaki T, Horiuchi M.
    • Organizer
      Asian Pacific Prion Symposium 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] プリオン感染初代培養神経細胞における神経細胞自律的変化の解析2020

    • Author(s)
      田中 美咲、山﨑 剛士、長谷部 理絵、鈴木 章夫、堀内 基広
    • Organizer
      第163回日本獣医学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 高濃度脳組織乳剤存在下でのreal-time quaking-induced conversion反応における全長組換えシカプリオンタンパク質固有の反応性2020

    • Author(s)
      鈴木章夫,澤田和平,山﨑剛士,堀内基広
    • Organizer
      第163回日本獣医学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] PrPSc-specific staining and transcriptome analyses, towards understanding mechanisms of prion propagation and neurodegeneration2019

    • Author(s)
      Horiuchi M, Suzuki A, Yamasaki T
    • Organizer
      Asian Pacific Prion Symposium 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Direct effects of generating PrPSc and consequences in neuron-enriched primary cultures2019

    • Author(s)
      Tanaka M, Yamasaki T, Suzuki A, Hasebe R, Horiuchi M
    • Organizer
      Asian Pacific Prion Symposium 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Characterization of gene expression profiles in brains of mice infected with typical and atypical BSEs2019

    • Author(s)
      Yamasaki T, Suzuki A, Hasebe R, Matsuura Y, Miyazawa K, Iwamaru Y, Horiuchi M
    • Organizer
      Prion2019
    • Related Report
      2019 Annual Research Report
  • [Presentation] Analysis of the unique reactivity of rCerPrP in real-time quaking-induced conversion reaction2019

    • Author(s)
      Suzuki A, Sawada K, Yamasaki T, Horiuchi M
    • Organizer
      Asian Pacific Prion Symposium 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Funded Workshop] Asian Pacific Prion Symposium 20212021

    • Related Report
      2021 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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