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Elucidation of the molecular pathogenesis of selective degeneration in multisystem proteinopathy and amyotrophic lateral sclerosis.

Research Project

Project/Area Number 20K07897
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

Warita Hitoshi  東北大学, 大学病院, 助教 (30400245)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords多系統蛋白質症 / 筋萎縮性側索硬化症 / 骨格筋 / RNA結合蛋白 / hnRNP / 運動ニューロン / オミックス解析 / トランスクリプトーム
Outline of Research at the Start

本研究では、HNRNPA1変異に伴う多系統蛋白質症(MSP)-筋萎縮性側索硬化症(ALS)で選択的変性に陥る細胞群(大脳皮質ニューロン,脊髄運動ニューロン,骨格筋細胞)と変性を免れやすい細胞群(外眼筋支配運動ニューロンや感覚ニューロン)を樹立済の自験MSP3および対照ヒトiPS細胞から分化誘導し、それらの比較研究から(1) 単純・共培養系+ストレス負荷における細胞表現型と分子細胞病理,各細胞間の相違,(2) 各細胞群の全トランスクリプトーム比較解析で抽出される病態関連分子とその相違,(3) 各細胞群においてhnRNPA1と相互作用するRNA種を明らかにして、治療標的分子の発見をめざす。

Outline of Final Research Achievements

To elucidate the cell-selective degeneration mechanism in multisystem proteinopathy (MSP) and amyotrophic lateral sclerosis (ALS), we established multiple lines of MSP3 patients-derived pluripotent stem cells (iPSCs). Motor neurons and skeletal muscle cells defferentiated from the MSP3-specific iPSCs and isogenic control cells were subjected to this study. After improving the efficiency of induction and differentiation into skeletal muscle cells and the long-term culture method, a comparative analyses was performed to reveal molecular cell pathology. As a result, we found that hnRNPA1 was localized to the cytoplasm under oxidative stress as a pathological phenotype of skeletal muscle cells.

Academic Significance and Societal Importance of the Research Achievements

本研究成果をふまえ、スペクトラムを形成しつつある多系統蛋白質症(MSP)-筋萎縮性側索硬化症(ALS)の原因遺伝子変異がもたらす細胞種選択的な変性メカニズムの解明と治療標的分子の発見につなげることで、治療法が未確立のこれら神経変性疾患のみならず、他の運動ニューロン疾患や骨格筋変性疾患の治療法開発にもつながる意義がある。

Report

(3 results)
  • 2022 Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (20 results)

All 2022 2021 2020 Other

All Journal Article (9 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 7 results) Presentation (6 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results) Book (1 results) Remarks (4 results)

  • [Journal Article] MOG Antibody-Associated Disorders Following SARS- CoV-2 Vaccination: A Case Report and Literature Review.2022

    • Author(s)
      Matsumoto Y, Ohyama A, Kubota T, Ikeda K, Kaneko K, Takai Y, Warita H, Takahashi T, Misu T, Aoki M.
    • Journal Title

      Front Neurol.

      Volume: 13 Pages: 845755-845755

    • DOI

      10.3389/fneur.2022.845755

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long-term outcomes after surgery to prevent aspiration for patients with amyotrophic lateral sclerosis2022

    • Author(s)
      Soga T, Suzuki N, Kato K, Kawamoto-Hirano A, Kawauchi Y, Izumi R, Toyoshima M, Mitsuzawa S, Shijo T, Ikeda K, Warita H, Katori Y, Aoki M, Kato M.
    • Journal Title

      BMC Neurology

      Volume: 22 Issue: 1 Pages: 94-94

    • DOI

      10.1186/s12883-022-02619-z

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Malignant otitis externa presenting cerebral infarction from pseudoaneurysm: A case report and a review of the literature2022

    • Author(s)
      Koshiba Y, Ikeda R, Suzuki J, Honkura Y, Funayama Y, Ikeda K, Warita H, Aoki M, Kawase T, Katori Y.
    • Journal Title

      Clinical Case Reports

      Volume: 10 Issue: 2

    • DOI

      10.1002/ccr3.5276

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel deletion in the C-terminal region of HSPB8 in a family with rimmed vacuolar myopathy2021

    • Author(s)
      Inoue-Shibui Aya、Niihori Tetsuya、Kobayashi Michio、Suzuki Naoki、Izumi Rumiko、Warita Hitoshi、Hara Kenju、Shirota Matsuyuki、Funayama Ryo、Nakayama Keiko、Nishino Ichizo、Aoki Masashi、Aoki Yoko
    • Journal Title

      Journal of Human Genetics

      Volume: NA Issue: 10 Pages: 965-972

    • DOI

      10.1038/s10038-021-00916-y

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Reduced PHOX2B stability causes axonal growth impairment in motor neurons with TARDBP mutations2021

    • Author(s)
      Mitsuzawa S, Suzuki N, Akiyama T, Ishikawa M, Sone T, Kawada J, Funayama R, Shirota M, Mitsuhashi H, Morimoto S, Ikeda K, Shijo T, Ohno A, Nakamura N, Ono H, Ono R, Osana S, Nakagawa T, Nishiyama A, Izumi R, Kaneda S, Ikeuchi Y, Nakayama K, Fujii T, Warita H, Okano H, Aoki M.
    • Journal Title

      Stem Cell Reports

      Volume: 16 Issue: 6 Pages: 1527-1541

    • DOI

      10.1016/j.stemcr.2021.04.021

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] RNP顆粒生成・分解からみた多系統蛋白質症2021

    • Author(s)
      割田仁, 池田謙輔, 青木正志
    • Journal Title

      脳神経内科

      Volume: 95 Pages: 112-120

    • Related Report
      2021 Research-status Report
  • [Journal Article] Generation of an ALS human iPSC line KEIOi001-A from peripheral blood of a Charcot disease-affected patient carrying TARDBP p.N345K heterozygous SNP mutation2020

    • Author(s)
      Leventoux Nicolas、Morimoto Satoru、Hara Kenju、Nakamura Shiho、Ozawa Fumiko、Mitsuzawa Shio、Akiyama Tetsuya、Nishiyama Ayumi、Suzuki Naoki、Warita Hitoshi、Aoki Masashi、Okano Hideyuki
    • Journal Title

      Stem Cell Research

      Volume: 47 Pages: 101896-101896

    • DOI

      10.1016/j.scr.2020.101896

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] An Amyotrophic Lateral Sclerosis-Associated Mutant of C21ORF2 Is Stabilized by NEK1-Mediated Hyperphosphorylation and the Inability to Bind FBXO32020

    • Author(s)
      Watanabe Y, Nakagawa T, Akiyama T, Nakagawa M, Suzuki N, Warita H, Aoki M, Nakayama K.
    • Journal Title

      iScience

      Volume: 23 Issue: 9 Pages: 1-15

    • DOI

      10.1016/j.isci.2020.101491

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Motor nerve organoid is useful tool to analyze axonal degeneration of ALS.2021

    • Author(s)
      Suzuki N, Kawada J, Akiyama T, Mitsuzawa S, Kato M, Warita H, Fujii T, Eggan K, Okano H, Aoki M.
    • Organizer
      第62回日本神経学会学術大会(62st Annual Meeting of the Japanese Society of Neurology)
    • Related Report
      2021 Research-status Report
  • [Presentation] Axonal growth impairment in iPS-derived motor neurons with TARDBP mutations.2021

    • Author(s)
      Mitsuzawa S, Suzuki N, Akiyama T, Ishikawa M, Sone T, Kawada J, Funayama R, Mitsuhashi H, Nishiyama A, Ikeda K, Shijo T, Nakamura N, Ono Y, Ono R, Izumi R, Ohno A, Nakagawa T, Nakayama K, Warita H, Okano H, Aoki M.
    • Organizer
      第62回日本神経学会学術大会(62st Annual Meeting of the Japanese Society of Neurology)
    • Related Report
      2021 Research-status Report
  • [Presentation] Reduced PHOX2B stability causes axonal growth impairment in motor neurons with TARDBP mutations.2021

    • Author(s)
      Mitsuzawa S, Suzuki N, Akiyama T, Ishikawa M, Sone T, Kawada J, Mitsuhashi H, Morimoto S, Ikeda K, Shijo T, Ohno A, Nakamura N, Ono H, Ono R, Nishiyama A, Izumi R, Kato M, Warita H, Okano H, Aoki M.
    • Organizer
      PACTALS 2021
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Reduced PHOX2B stability causes axonal growth impairment in motor neurons with ALS-linked TARDBP mutations.2021

    • Author(s)
      Mitsuzawa S, Suzuki N, Akiyama T, Ishikawa M, Sone T, Kawada J, Mitsuhashi H, Morimoto S, Ikeda K, Shijo T, Ohno A, Nakamura N, Ono H, Ono R, Nishiyama A, Izumi R, Kaneda S, Ikeuchi Y, Nakayama K, Fujii T, Warita H, Okano H, Aoki M.
    • Organizer
      ISSCR 2021 Tokyo
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Axonal growth impairment in motor neurons with TARDBP mutations were mediated by PHOX2B downregulation.2021

    • Author(s)
      Mitsuzawa S, Suzuki N, Akiyama T, Ishikawa M, Sone T, Kawada J, Funayama R, Shirota M, Mitsuhashi H, Morimoto S, Ikeda K, Shijo T, Ohno A, Nakamura N, Ono H, Ono R, Nishiyama A, Izumi R, Kaneda S, Ikeuchi Y, Nakayama K, Fujii T, Kato M, Warita H, Okano H, Aoki M.
    • Organizer
      32th International Symposium on ALS/MND
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] ALSに対する肝細胞増殖因子(HGF)脊髄腔内反復投与の第II相試験2020

    • Author(s)
      割田 仁
    • Organizer
      第61回日本神経学会学術大会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Book] 脳神経疾患最新の治療2021-20232020

    • Author(s)
      割田 仁,青木正志(分担執筆,園生雅弘・北川一夫・青木正志 共同編集)
    • Total Pages
      368
    • Publisher
      南江堂
    • ISBN
      4524227857
    • Related Report
      2020 Research-status Report
  • [Remarks] 東北大学神経内科

    • URL

      http://www.neurol.med.tohoku.ac.jp/index.html

    • Related Report
      2021 Research-status Report 2020 Research-status Report
  • [Remarks] Researchmap

    • URL

      https://researchmap.jp/warita_2012

    • Related Report
      2021 Research-status Report 2020 Research-status Report
  • [Remarks] ResearchGate

    • URL

      https://www.researchgate.net/profile/Hitoshi-Warita

    • Related Report
      2021 Research-status Report 2020 Research-status Report
  • [Remarks] ORCiD

    • URL

      https://orcid.org/0000-0001-7934-3863

    • Related Report
      2021 Research-status Report 2020 Research-status Report

URL: 

Published: 2020-04-28   Modified: 2025-01-30  

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