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Molecular pathophysiology of amyotrophic lateral sclerosis

Research Project

Project/Area Number 18K07537
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52020:Neurology-related
Research InstitutionTokyo Medical University

Principal Investigator

Aizawa Hitoshi  東京医科大学, 医学部, 主任教授 (10292103)

Co-Investigator(Kenkyū-buntansha) 郭 伸  東京医科大学, 医学部, 特任教授 (40160981)
Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords筋萎縮性側索硬化症 / ADAR2 / Pin 1 / TDP-43 / 孤発性筋萎縮性側索硬化症 / Pin1 / nucleoporin / nuclear isomerase Pin1 / importin-α4
Outline of Final Research Achievements

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. Selective deficiency of edited adenosine deaminase acting on RNA 2 (ADAR2), a key molecule in the acquisition of Ca2+ resistance in motor neurons has been reported in sporadic ALS (sALS) spinal motor neurons. ADAR2 activity is positively regulated by prolyl isomerase Pin1, a known phosphorylation-dependent peptidyl-prolyl cis/trans isomerase. In sALS, neurons expressing high Pin1 levels had TDP-43 inclusions, a pathological marker of ding motor neurons, more frequently than those without high Pin1 expression. These results suggest that the higher Pin1 expression in motor neurons with TDP-43 pathology from sALS patients may represent a compensatory mechanism.

Academic Significance and Societal Importance of the Research Achievements

孤発性筋萎縮性側索硬化症(ALS)は運動ニューロンの変性脱落により全身の筋力低下をきたし2-5年で呼吸不全に陥る疾患であるが、現在まで臨床的に効果的治療法は存在しない。孤発性ALSではRNA編集酵素であるadenosine deaminase acting on RNA2(ADAR2)の酵素活性の低下が運動ニューロン死の原因と考えられるが、ADAR2活性を制御する因子の解析がなされていなかった。本研究により病的運動ニューロンにおいてADAR2を制御するPin 1の発現が亢進していることを明らかにした。孤発性ALSの病態の解明に寄与するとともに新規治療薬に結び付く結果と考えられる。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (20 results)

All 2022 2021 2020 2019

All Journal Article (17 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 15 results,  Open Access: 5 results) Presentation (3 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Prolyl isomerase Pin1 expression in the spinal motor neurons of patients with sporadic amyotrophic lateral sclerosis2022

    • Author(s)
      Haruhisa Kato, Makiko Naito, Tomoko Saito, Takuto Hideyama, Yasuhiro Suzuki, Takashi Kimura, Shin Kwak, Hitoshi Aizawa
    • Journal Title

      J Clinical Neurology

      Volume: in press

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Nuclear pore destruction and loss of nuclear TDP-43 in FUS mutation-related amyotrophic lateral sclerosis motor neurons2022

    • Author(s)
      Aizawa Hitoshi、Teramoto Sayaka、Hideyama Takuto、Kato Haruhisa、Terashi Hiroo、Suzuki Yasuhiro、Kimura Takashi、Kwak Shin
    • Journal Title

      Journal of the Neurological Sciences

      Volume: 436 Pages: 120187-120187

    • DOI

      10.1016/j.jns.2022.120187

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Low-dose statin therapy for intracranial artery stenosis: A single center preliminary study2022

    • Author(s)
      Aizawa Hitoshi、Taguchi Takeshi、Ido Nobuhiro、Kato Haruhisa、Terashi Hiroo
    • Journal Title

      Journal of the Neurological Sciences

      Volume: 432 Pages: 120075-120075

    • DOI

      10.1016/j.jns.2021.120075

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Persistent Hemichorea as a Preceding Symptom of Cerebral Infarction Due to Middle Cerebral Artery Stenosis2021

    • Author(s)
      Ueta Yuki、Kato Haruhisa、Naito Makiko、Taguchi Takeshi、Terashi Hiroo、Aizawa Hitoshi
    • Journal Title

      Internal Medicine

      Volume: 60 Issue: 23 Pages: 3805-3808

    • DOI

      10.2169/internalmedicine.7191-21

    • NAID

      130008123591

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2021-12-01
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Characteristics of sagittal spinopelvic alignment in patients with Parkinson's disease2021

    • Author(s)
      Terashi Hiroo、Endo Kenji、Kato Haruhisa、Ido Nobuhiro、Aizawa Hitoshi
    • Journal Title

      Acta Neurologica Scandinavica

      Volume: 145 Issue: 1 Pages: 53-62

    • DOI

      10.1111/ane.13521

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Relationship between 123I-FP-CIT-SPECT and motor severity in drug-naive patients with Parkinson's disease2021

    • Author(s)
      Terashi Hiroo、Taguchi Takeshi、Ueta Yuki、Mitoma Hiroshi、Aizawa Hitoshi
    • Journal Title

      Journal of the Neurological Sciences

      Volume: 426 Pages: 117476-117476

    • DOI

      10.1016/j.jns.2021.117476

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis2021

    • Author(s)
      Aizawa H, Kato H, Oba K, Kawahara T, Okubo Y, Saito T, Naito M, Urushitani M, Tamaoka A, Nakamagoe K, Ishii K, Kanda T, Katsuno M, Atsuta N, Maeda Y, Nagai M, Nishiyama K, Ishiura H, Toda T, Kawata A, Abe K, Yabe I, Takahashi-Iwata I, Sasaki H, Warita H, Aoki M, Sobue G, Mizusawa H, Matsuyama Y, Haga T, Kwak S
    • Journal Title

      Journal of Neurology

      Volume: 269 Issue: 2 Pages: 885-896

    • DOI

      10.1007/s00415-021-10670-y

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1.2021

    • Author(s)
      Hayashida A, Li Y, Yoshino H, Daida K, Ikeda A, Ogaki K, Fuse A, Mori A, Takanashi M, Nakahara T, Yoritaka A, Tomizawa Y, Furukawa Y, Kanai K, Nakayama Y, Ito H, Ogino M, Hattori Y, Hattori T,Ichinose Y, Takiyama Y, Saito T, Kimura T, Aizawa H, et al.
    • Journal Title

      Neurobiology in Aging

      Volume: 146

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Impact of the catechol-O-methyltransferase Val158Met polymorphism on the pharmacokinetics of l-dopa and its metabolite 3-O-methyldopa in combination with entacapone2020

    • Author(s)
      Yamamoto Joe、Omura Tomohiro、Kasamo Sachiko、Yamamoto Shota、Kawata Masayoshi、Yonezawa Atsushi、Taruno Yosuke、Endo Hisako、Aizawa Hitoshi、Sawamoto Nobukatsu、Matsubara Kazuo、Takahashi Ryosuke、Tasaki Yoshikazu
    • Journal Title

      Journal of Neural Transmission

      Volume: 128 Issue: 1 Pages: 27-36

    • DOI

      10.1007/s00702-020-02267-y

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Analysis of non-invasive gait recording under free-living conditions in patients with Parkinson's disease: relationship with global cognitive function and motor abnormalities.2020

    • Author(s)
      Terashi H, Taguchi T, Ueta Y, Okubo Y, Mitoma H, Aizawa H.
    • Journal Title

      BMC Neurol

      Volume: 20 Issue: 1 Pages: 161-161

    • DOI

      10.1186/s12883-020-01729-w

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Assessment and Rating of Motor Cerebellar Ataxias With the Kinect v2 Depth Sensor: Extending Our Appraisal2020

    • Author(s)
      Honda Takeru、Mitoma Hiroshi、Yoshida Hirotaka、Bando Kyota、Terashi Hiroo、Taguchi Takeshi、Miyata Yohane、Kumada Satoko、Hanakawa Takashi、Aizawa Hitoshi、Yano Shiro、Kondo Toshiyuki、Mizusawa Hidehiro、Manto Mario、Kakei Shinji
    • Journal Title

      Frontiers in Neurology

      Volume: 11 Pages: 1-14

    • DOI

      10.3389/fneur.2020.00179

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Suitable indications of eculizumab for patients with refractory generalized myasthenia gravis2020

    • Author(s)
      Oyama M, Okada K, Masuda M, Shimizu Y, Yokoyama K, Uzawa A, Kawaguchi N, Ikeguchi R, Hoshino Y, Hatano T, Ozawa Y, Nakahara J, Aizawa H, Kitagawa K, Hattori N, Kuwabara S, Murai H, Suzuki S
    • Journal Title

      Therapeutic Advances in Neurological Disorders

      Volume: 13 Pages: 1-9

    • DOI

      10.1177/1756286420904207

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Underlying embolic and pathologic differentiation by cerebral microbleeds in cryptogenic stroke2020

    • Author(s)
      Kikuno Muneaki、Ueno Yuji、Shimizu Takahiro、Kuriki Ayako、Tateishi Yohei、Doijiri Ryosuke、Shimada Yoshiaki、Takekawa Hidehiro、Yamaguchi Eriko、Koga Masatoshi、Kamiya Yuki、Ihara Masafumi、Tsujino Akira、Hirata Koichi、Toyoda Kazunori、Hasegawa Yasuhiro、Aizawa Hitoshi、Hattori Nobutaka、Urabe Takao
    • Journal Title

      Journal of Neurology

      Volume: 267 Issue: 5 Pages: 1482-1490

    • DOI

      10.1007/s00415-020-09732-4

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] 筋萎縮性側索硬化症への挑戦2020

    • Author(s)
      相澤 仁志
    • Journal Title

      東京都医師会雑誌

      Volume: 73 Pages: 5-7

    • Related Report
      2019 Research-status Report
  • [Journal Article] Association of daily physical activity with cognition and mood disorders in treatment-naive patients with early-stage Parkinson’s disease2019

    • Author(s)
      Terashi Hiroo、Taguchi Takeshi、Ueta Yuki、Mitoma Hiroshi、Aizawa Hitoshi
    • Journal Title

      Journal of Neural Transmission

      Volume: 126 Issue: 12 Pages: 1617-1624

    • DOI

      10.1007/s00702-019-02085-x

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] 孤発性ALSに対するペランパネル2019

    • Author(s)
      相澤 仁志、郭 伸
    • Journal Title

      Brain and Nerve

      Volume: 71 Pages: 1270-1278

    • Related Report
      2019 Research-status Report
  • [Journal Article] Impaired Nucleoporins Are Present in Sporadic Amyotrophic Lateral Sclerosis Motor Neurons that Exhibit Mislocalization of the 43-kDa TAR DNA-Binding Protein.2019

    • Author(s)
      Aizawa H, Yamashita T, Kato H, Kimura T, Kwak S
    • Journal Title

      J Clin Neurol.

      Volume: 15(1) Issue: 1 Pages: 62-67

    • DOI

      10.3988/jcn.2019.15.1.62

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] A Phase II Clinical Trial of Perampanel for Sporadic Amyotrophic Lateral Sclerosis2020

    • Author(s)
      Aizawa H, Kato H, Oba K, Kawahara T, Okubo Y, Saito T, Naito M, Urushitani M, Tamaoka A, Nakamagoe K, Ishii K, Kanda T, Katsuno M, Atsuta N, Maeda Y, Nagai M, Nishiyama K, Ishiura H, MD, Toda T, et al.
    • Organizer
      31th International symposium on ALS/MND
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] PERAMPANEL FOR SPORADIC AMYOTROPHIC LATERAL SCLEROSIS2020

    • Author(s)
      Aizawa H, Kato H, Oba K, Kawahara T, Okubo Y, Saito T, Naito M, Urushitani M, Tamaoka A, Nakamagoe K, Ishii K, Kanda T, Katsuno M, Atsuta N, Maeda Y, Nagai M, Nishiyama K, Ishiura H, MD, Toda T, et al.
    • Organizer
      2020 Annual Meeting of Neurology
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Disrupted nuclear pore complex with mislocalization of TDP-43 in sporadic amyotrophic lateral sclerosis motor neurons2019

    • Author(s)
      Aizawa H, Yamashita T, Kato H, Kimura T, Saito T, Teramoto S, Kwak S.
    • Organizer
      第60回日本神経病理学会
    • Related Report
      2019 Research-status Report

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Published: 2018-04-23   Modified: 2023-01-30  

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