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Novel therapy for progressive multiple sclerosis and multiple system atrophy by glial regulation

Research Project

Project/Area Number 20K07889
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

Katsuhisa Masaki  九州大学, 大学病院, 講師 (90612903)

Co-Investigator(Kenkyū-buntansha) 山口 浩雄  九州大学, 大学病院, 特任講師 (00701830)
山崎 亮  九州大学, 医学研究院, 准教授 (10467946)
渡邉 充  九州大学, 大学病院, 助教 (30748009)
吉良 潤一  国際医療福祉大学, 福岡薬学部, 教授 (40183305)
松瀬 大  九州大学, 医学研究院, 助教 (70596395)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords多系統萎縮症 / コネキシン / ギャップ結合 / グリア細胞 / シヌクレイン / オリゴデンドロサイト / アストロサイト / 多発性硬化症 / グリア炎症
Outline of Research at the Start

私たちはオリゴデンドログリアでヒト変異αシヌクレインを発現させることで進行型多発性硬化症および小脳型多系統萎縮症を呈する新たなモデルマウスの開発に成功した。本モデルは小脳性運動失調や運動麻痺が明らかであり、発病や進行も早いことからヒト病態をより反映し、かつ治療法開発に有用である。オリゴデンドログリアにヒト変異αSynが発現すると、脱髄やオリゴデンドロサイト細胞死に先行してarginase-1陽性ミクログリアの顕著な活性化やグリア細胞間情報伝達を担うコネキシン群が広汎に脱落することを見出しており、αSynと脳内恒常性グリアネットワーク破綻という新しい視点から病態解明と新規治療法開発を推進する。

Outline of Final Research Achievements

The pathological hallmark of multiple system atrophy (MSA) is aberrant accumulation of phosphorylated α-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions (GCIs). Extensive demyelination occurs in the olivopontocerebellar and striatonigral pathways. Glial connexins (Cxs) play critical roles in myelin maintenance, and have not been studied in MSA. We investigated glial Cx changes in 15 autopsied patients with MSA. We classified lesions into three stages: early (Stage I), intermediate (Stage II), and late (Stage III) stages. Accumulation of phosphorylated α-synuclein in oligodendrocytes was frequently seen in Stage I but less frequently observed in Stages II and III. Even at Stage I, Cx32 was nearly absent from myelin. Cx32 was re-distributed in the oligodendrocyte cytoplasm and co-localized with GCIs. Astrocytic Cx43 was down-regulated in Stage I.Early and extensive alterations of glial Cxs occur in MSA and may accelerate demyelination.

Academic Significance and Societal Importance of the Research Achievements

多系統萎縮症は未だ原因不明の進行性神経変性疾患であり、病態解明や新規治療法開発が大きく期待されている。今回の研究成果は多系統萎縮症における脱髄や神経細胞脱落の病態を考える上で全く新しい機序を提唱したものであり、実際に多系統萎縮症剖検例で検討したことも大きな成果である。今後はギャップ結合やコネキシンに着目した新規治療法開発を推進する。

Report

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

    (25 results)

All 2023 2022 2021 2020

All Journal Article (19 results) (of which Int'l Joint Research: 10 results,  Peer Reviewed: 19 results,  Open Access: 12 results) Presentation (4 results) Book (2 results)

  • [Journal Article] Effect of smoking on disease activity in multiple sclerosis patients treated with dimethyl fumarate or fingolimod2023

    • Author(s)
      Tanaka E, Watanabe M, Fukumoto S, Masaki K, Yamasaki R, Matsushita T, Isobe N
    • Journal Title

      Mult Scler Relat Disord

      Volume: - Pages: 104513-104513

    • DOI

      10.1016/j.msard.2023.104513

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Connexin 30 Deficiency Ameliorates Disease Progression at the Early Phase in a Mouse Model of Amyotrophic Lateral Sclerosis by Suppressing Glial Inflammation2022

    • Author(s)
      Yu Hashimoto, Ryo Yamasaki, Senri Ko, Eriko Matsuo, Yuko Kobayakawa, Katsuhisa Masaki, Dai Matsuse, Noriko Isobe
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 24 Pages: 16046-16046

    • DOI

      10.3390/ijms232416046

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Early and extensive alterations of glial connexins, distal oligodendrogliopathy type demyelination, and nodal/paranodal pathology are characteristic of multiple system atrophy2022

    • Author(s)
      Yuji Nishimura, Katsuhisa Masaki, Dai Matsuse, Hiroo Yamaguchi, Tatsunori Tanaka1, Eriko Matsuo, Shotaro Hayashida, Mitsuru Watanabe, Takuya Matsushita, Shoko Sadashima, Naokazu Sasagasako, Ryo Yamasaki, Noriko Isobe, Toru Iwaki, Jun-ichi Kira
    • Journal Title

      Brain Pathology

      Volume: - Issue: 3 Pages: 1-16

    • DOI

      10.1111/bpa.13131

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Teaching Video NeuroImage: Reversible Parkinsonism Caused by Lumboperitoneal Shunt Overdrainage.2022

    • Author(s)
      Takeuchi H, Masaki K, Ogata H, Nagata S, Shimogawa T, Yamasaki R, Isobe N.
    • Journal Title

      Neurology.

      Volume: 99 Issue: 11 Pages: 486-488

    • DOI

      10.1212/wnl.0000000000200994

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Shadowboxing-induced reflex seizures in a patient with focal epilepsy.2022

    • Author(s)
      Okadome T, Takeuchi H, Yamaguchi T, Mukaino T, Ogata H, Masaki K, Shigeto H, Isobe N.
    • Journal Title

      Epilepsy Behav Rep.

      Volume: 19 Pages: 100543-100543

    • DOI

      10.1016/j.ebr.2022.100543

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Choroid Plexus Volume in Multiple Sclerosis vs Neuromyelitis Optica Spectrum Disorder: A Retrospective, Cross-sectional Analysis2022

    • Author(s)
      Fukumoto S, Watanabe M, Masaki K, Matsushita T, Isobe N, Kira JI, et al.
    • Journal Title

      Neurol Neuroimmunol Neuroinflamm

      Volume: 9 Issue: 3

    • DOI

      10.1212/nxi.0000000000001147

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Serum anti-oligodendrocyte autoantibodies in patients with multiple sclerosis detected by a tissue-based immunofluorescence assay2021

    • Author(s)
      Miyachi Y, Fujii T, Yamasaki R, Tsuchimoto D, Iinuma K, Sakoda A, Fukumoto S, Matsushita T, Masaki K, Isobe N, Nakabeppu Y, Kira J.
    • Journal Title

      Front Neurol

      Volume: 12 Pages: 681980-681980

    • DOI

      10.3389/fneur.2021.681980

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Brain gray matter astroglia-specific connexin 43 ablation attenuates spinal cord inflammatory demyelination.2021

    • Author(s)
      Une H, Yamasaki R, Nagata S, Yamaguchi H, Nakamuta Y, Indiasari UC, Cui YW, Shinoda K, Masaki K, Gotz M, Kira J:
    • Journal Title

      J Neuroinflammation

      Volume: 18 Issue: 1 Pages: 126-126

    • DOI

      10.1186/s12974-021-02176-1

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Eculizumab in refractory generalized myasthenia gravis previously treated with rituximab: subgroup analysis of REGAIN and its extension study.2021

    • Author(s)
      Siddiqi ZA, Nowak RJ, Mozaffar T, O'Brien F, Yountz M, Patti F; REGAIN Study Group.
    • Journal Title

      Muscle Nerve

      Volume: 64 Issue: 6 Pages: 662-669

    • DOI

      10.1002/mus.27422

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Distinct microglial and macrophage distribution patterns in the concentric and lamellar lesions in Bal?'s disease and neuromyelitis optica spectrum disorders2020

    • Author(s)
      Hayashida Shotaro、Masaki Katsuhisa、Suzuki Satoshi O.、Yamasaki Ryo、Watanabe Mitsuru、Koyama Sachiko、Isobe Noriko、Matsushita Takuya、Takahashi Kazuya、Tabira Takeshi、Iwaki Toru、Kira Jun‐ichi
    • Journal Title

      Brain Pathology

      Volume: 30 Issue: 6 Pages: 1144-1157

    • DOI

      10.1111/bpa.12898

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genetic factors for susceptibility to and manifestations of neuromyelitis optica2020

    • Author(s)
      Matsushita Takuya、Masaki Katsuhisa、Isobe Noriko、Sato Shinya、Yamamoto Ken、Nakamura Yuri、Watanabe Mitsuru、Suenaga Toshihiko、Kira Jun‐ichi、the Japan Multiple Sclerosis Genetic Consortium
    • Journal Title

      Annals of Clinical and Translational Neurology

      Volume: 7 Issue: 11 Pages: 2082-2093

    • DOI

      10.1002/acn3.51147

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Connexins in neuromyelitis optica: a link between astrocytopathy and demyelination2020

    • Author(s)
      Richard Chloe、Ruiz Anne、Cavagna Sylvie、Bigotte Maxime、Vukusic Sandra、Masaki Katsuhisa、Suenaga Toshihiko、Kira Jun-Ichi、Giraudon Pascale、Marignier Romain
    • Journal Title

      Brain

      Volume: 143 Issue: 9 Pages: 2721-2732

    • DOI

      10.1093/brain/awaa227

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] RNA-binding protein altered expression and mislocalization in MS2020

    • Author(s)
      Masaki Katsuhisa、Sonobe Yoshifumi、Ghadge Ghanashyam、Pytel Peter、L?pine Paula、Pernin Florian、Cui Qiao-Ling、Antel Jack P.、Zandee Stephanie、Prat Alexandre、Roos Raymond P.
    • Journal Title

      Neurology - Neuroimmunology Neuroinflammation

      Volume: 7 Issue: 3

    • DOI

      10.1212/nxi.0000000000000704

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oligodendroglial connexin 47 regulates neuroinflammation upon autoimmune demyelination in a novel mouse model of multiple sclerosis2020

    • Author(s)
      Zhao Y, Yamasaki R, Yamaguchi H, Nagata S, Une H, Cui Y, Masaki K, Nakamuta Y, Iinuma K, Watanabe M, Matsushita T, Isobe N, Kira J.
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 117 Issue: 4 Pages: 2160-2169

    • DOI

      10.1073/pnas.1901294117

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Environmental risk factors for multiple sclerosis in Japanese people2020

    • Author(s)
      Sakoda A, Matsushita T, Nakamura Y, Watanabe M, Shinoda K, Masaki K, Isobe N, Yamasaki R, Kira J.
    • Journal Title

      Multiple Sclerosis and Related Disorders

      Volume: 38 Pages: 101872-101872

    • DOI

      10.1016/j.msard.2019.101872

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Contribution of cortical lesions to cognitive impairment in Japanese patients with multiple sclerosis2020

    • Author(s)
      Shinoda K, et al.
    • Journal Title

      Sci Rep

      Volume: 10 Issue: 1 Pages: 5228-5228

    • DOI

      10.1038/s41598-020-61012-3

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Early decrease in intermediate monocytes in peripheral blood is characteristic of multiple system atrophy-cerebellar type2020

    • Author(s)
      Dai Matsuse, Ryo Yamasaki, Guzailiayi Maimaitijiang, Hiroo Yamaguchi, Katsuhisa Masaki, Noriko Isobe, Takuya Matsushita, Jun-ichi Kira
    • Journal Title

      Journal of Neuroimmunology

      Volume: 349 Pages: 577395-577395

    • DOI

      10.1016/j.jneuroim.2020.577395

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] The accumulation of advanced glycation end-products in a schizophrenic patient with a glyoxalase 1 frameshift mutation: An autopsy study.2020

    • Author(s)
      Torii Y, Iritani S, Sekiguchi H, Habuchi C, Fujishiro H, Kushima I, Kawakami I, Itokawa M, Arai M, Hayashida S, Masaki K, Kira JI, Kawashima K, Ozaki N.
    • Journal Title

      Schizophr Res.

      Volume: 223 Pages: 356-358

    • DOI

      10.1016/j.schres.2020.09.012

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Morphological alteration of myelin-oligodendrocytes in a schizophrenic patient with 22q11.2 deletion syndrome: An autopsy study2020

    • Author(s)
      Torii Youta、Iritani Shuji、Marui Tomoyasu、Sekiguchi Hirotaka、Habuchi Chikako、Fujishiro Hiroshige、Kushima Itaru、Oshima Kenichi、Niizato Kazuhiro、Hayashida Shotaro、Masaki Katsuhisa、Kira Jun-ichi、Yoshida Mari、Ozaki Norio
    • Journal Title

      Schizophrenia Research

      Volume: 223 Pages: 353-355

    • DOI

      10.1016/j.schres.2020.07.003

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] 多系統萎縮症におけるconnexin蛋白群の早期かつ広範な変化と脱髄病態との関連2022

    • Author(s)
      西村 由宇慈, 眞崎 勝久, 松瀬 大, 山口 浩雄, 田中 辰典, 貞島 祥子, 笹ヶ迫 直一, 山崎 亮, 磯部 紀子, 岩城 徹, 吉良 潤一
    • Organizer
      第34回日本神経免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 中枢神経脱髄におけるオリゴデンドログリア変性によるミクログリア活性化メカニズムの解明2022

    • Author(s)
      松下 拓也, 西村 由宇慈, 眞崎 勝久, 松瀬 大, 山口 浩雄, 吉良 潤一, 磯部 紀子
    • Organizer
      第34回日本神経免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 小脳型多系統萎縮症モデルマウスを用いた新規創薬ターゲットの探索2022

    • Author(s)
      山口 浩雄, 西村 由宇慈, 松瀬 大, 眞崎 勝久, 田中 辰典, 雑賀 徹, 原田 雅也, 田中 謙二, 山埼 亮, 磯部 紀子, 吉良 潤一
    • Organizer
      第40回日本神経治療学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 当科で経験したBalo病6例の臨床的特徴および画像所見に関する検討2022

    • Author(s)
      眞崎 勝久, 松下 拓也, 渡邉 充, 福元 尚子, 田中 栄蔵, 磯部 紀子
    • Organizer
      第63回日本神経学会学術大会
    • Related Report
      2022 Annual Research Report
  • [Book] 日本臨床【免疫性神経疾患(第2版)-基礎・臨床の最新知見-】中枢神経脱髄疾患 Tumefactive MS、Balo病2022

    • Author(s)
      林田 翔太郎, 眞崎 勝久
    • Total Pages
      6
    • Publisher
      日本臨床社
    • Related Report
      2022 Annual Research Report
  • [Book] 日本臨床【免疫性神経疾患(第2版)-基礎・臨床の最新知見-】中枢神経脱髄疾患 多発性硬化症の病態・病理2022

    • Author(s)
      眞崎 勝久
    • Total Pages
      8
    • Publisher
      日本臨床社
    • Related Report
      2022 Annual Research Report

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

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