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Clarify the pathological mechanism for autoimmune encephalitis using recombinant autoantibodies

Research Project

Project/Area Number 19K22548
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 49:Pathology, infection/immunology, and related fields
Research InstitutionNational Institute for Physiological Sciences

Principal Investigator

Fukata Masaki  生理学研究所, 分子細胞生理研究領域, 教授 (00335027)

Project Period (FY) 2019-06-28 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Keywords自己免疫性脳炎 / LGI1 / GABAa受容体 / 組換え抗体 / シナプス / けいれん / 記憶障害
Outline of Research at the Start

自己免疫性脳炎は、けいれん、記憶障害、見当識障害など多様な症状を示す重篤な脳疾患である。最近、私共を含めた研究により、様々なシナプス蛋白質(NMDA受容体、LGI1、GABA受容体等)に対する自己抗体が次々と同定されてきた。本研究では、患者由来の組換え型自己抗体を活用し、分子、神経細胞、神経回路、動物個体レベルでの標的蛋白質の生理機能や自己抗体の病態機構を明らかにしていく。

Outline of Final Research Achievements

Autoimmune encephalitis presenting with amnesia, seizures, and disorientation is highly topical in basic and clinical neuroscience. Recent studies have identified numerous associated autoantibodies, targeting synaptic proteins including neurotransmitter receptors and a secreted protein, LGI1. Here, by collaborating with Germany group, we isolated various recombinant monoclonal antibodies from patients' B cells with autoimmune encephalitis. Taking advantage of these antibodies, we elucidated patho-physiological mechanisms for autoimmune encephalitis.

Academic Significance and Societal Importance of the Research Achievements

私共は、共同研究者のPruss博士らよって単離された組換え型モノクロナール抗体の中から、LGI1や、GABAa受容体、NMDA受容体に反応する自己抗体に関して、その反応特異性、抗原部位の同定、抗原-抗体間の親和性の評価等を行い、自己抗体の作用機序の解明に大きく貢献した。これらの研究成果は、Ann Neurol誌、PNAS誌、J Exp Med誌に国際共著論文として発表され、自己免疫性脳炎の病態解明に大きく貢献した。

Report

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

    (49 results)

All 2022 2021 2020 2019 Other

All Int'l Joint Research (17 results) Journal Article (19 results) (of which Int'l Joint Research: 14 results,  Peer Reviewed: 17 results,  Open Access: 13 results) Presentation (7 results) (of which Int'l Joint Research: 4 results,  Invited: 6 results) Book (1 results) Remarks (5 results)

  • [Int'l Joint Research] DZNE/Charite-Universitatsmedizin(ドイツ)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] UCSF(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] UCL/The University of Edinburgh(英国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] IST(オーストリア)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Aarhus University(デンマーク)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research]

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] UCSF/UCSD(米国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] DZNE(ドイツ)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] IST(オーストリア)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] UCL/The University of Edinburgh(英国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] University of Helsinki(フィンランド)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] UCSF/Chicago University(米国)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] Institut Curie(フランス)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] DZNE(ドイツ)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] UCL Institute of Neurology(英国)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] University of Helsinki(フィンランド)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research]

    • Related Report
      2019 Research-status Report
  • [Journal Article] Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy2022

    • Author(s)
      van der Knoop M Marieke M*、Maroofian Reza*、Fukata Yuko*、van Ierland Yvette、Karimiani G Ehsan、Lehesjoki Anna-Elina、Muona Mikko、Paetau Anders、Miyazaki Yuri、Hirano Yoko、Selim Laila、-----32名-----、Striano Pasquale、Severino Mariasavina、Fukata Masaki#、Hilhorst-Hofstee Yvonne#、Houlden Henry#
    • Journal Title

      Brain

      Volume: - Issue: 7 Pages: 2301-2312

    • DOI

      10.1093/brain/awac116

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Encephalitis patient-derived monoclonal GABAa receptor antibodies cause epileptic seizures Journal of Experimental Medicine2021

    • Author(s)
      Kreye Jakob、Wright K Sukhvir、van Casteren Adriana、Stoffler Laura、Machule Marie-Luise、Reincke S Momsen、Nikolaus Marc、van Hoof Scott、Sanchez-Sendin Elisa、Homeyer A Marie、Cordero Gomez Cesar、Kornau Hans-Christian、-----12名-----、Wickel Jonathan、Geis Christian、Fukata Yuko、Fukata Masaki、Pruss Harald
    • Journal Title

      Journal of Experimental Medicine

      Volume: 218

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] 14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice2021

    • Author(s)
      Norihiko Yokoi, Yuko Fukata, Kei Okatsu, Atsushi Yamagata, Yan Liu , Makoto Sanbo, Yuri Miyazaki, Teppei Goto, Manabu Abe , Hidetoshi Kassai, Kenji Sakimura, Dies Meijer, Masumi Hirabayashi, Shuya Fukai, Masaki Fukata
    • Journal Title

      Cell Reports

      Volume: 37 Issue: 11 Pages: 110107-110107

    • DOI

      10.1016/j.celrep.2021.110107

    • NAID

      120007177780

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A novel red fluorescence dopamine biosensor selectively detects dopamine in the presence of norepinephrine in vitro2021

    • Author(s)
      Nakamoto Chihiro、Goto Yuhei、Tomizawa Yoko、Fukata Yuko、Fukata Masaki、Harpsoe Kasper、Gloriam David E.、Aoki Kazuhiro、Takeuchi Tomonori
    • Journal Title

      Molecular Brain

      Volume: 14 Issue: 1 Pages: 173-173

    • DOI

      10.1186/s13041-021-00882-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] MAGUKs are essential, but redundant, in long-term potentiation2021

    • Author(s)
      Chen Xiumin、Fukata Yuko、Fukata Masaki、Nicoll Roger A.
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 118 Issue: 28

    • DOI

      10.1073/pnas.2107585118

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Trans-synaptic LGI1-ADAM22?MAGUK in AMPA and NMDA receptor regulation2021

    • Author(s)
      Fukata Yuko、Hirano Yoko、Miyazaki Yuri、Yokoi Norihiko、Fukata Masaki
    • Journal Title

      Neuropharmacology

      Volume: 194 Pages: 108628-108628

    • DOI

      10.1016/j.neuropharm.2021.108628

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention2021

    • Author(s)
      Fukata Yuko、Chen Xiumin、Chiken Satomi、Hirano Yoko、Yamagata Atsushi、Inahashi Hiroki、Sanbo Makoto、Sano Hiromi、Goto Teppei、Hirabayashi Masumi、Kornau Hans-Christian、Pruss Harald、Nambu Atsushi、Fukai Shuya、Nicoll Roger A.、Fukata Masaki
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 118 Issue: 3 Pages: 1-12

    • DOI

      10.1073/pnas.2022580118

    • NAID

      120006976050

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice2021

    • Author(s)
      Yoshida T, Yamagata A, Imai A, Kim J, Izumi H, Nakashima S, Shiroshima T, Maeda A, Iwasawa-Okamoto S, Azechi K, Osaka F, Saitoh T, Maenaka K, Shimada T, Fukata Y, Fukata M, Matsumoto J, Nishijo H, Takao K, Tanaka S, Okabe S, Tabuchi K, Uemura T, Mishina M, Mori H & Fukai S
    • Journal Title

      Nature Communications

      Volume: 12(1) Issue: 1 Pages: 1848-1848

    • DOI

      10.1038/s41467-021-22059-6

    • NAID

      120006996978

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Encephalitis patient derived monoclonal GABAA receptor antibodies cause catatonia and epileptic seizures2021

    • Author(s)
      Kreye Jakob、Wright Sukhvir K.、van Casteren Adriana、Machule Marie-Luise、Reincke S. Momsen、Nikolaus Marc、Stoffler Laura、van Hoof Scott、Sanchez-Sendin Elisa、Kornau Hans-Christian、Kaindl Angela M.、Wilson Max A.、Greenhill Stuart、他5名、Geis Christian、Fukata Yuko、Fukata Masaki、Pruss Harald
    • Journal Title

      bioRxiv

      Volume: -

    • DOI

      10.1101/2021.01.28.428602

    • Related Report
      2020 Research-status Report
    • Open Access / Int'l Joint Research
  • [Journal Article] APEGS法によるタンパク質パルミトイル化修飾の定量2021

    • Author(s)
      深田正紀、横井紀彦、深田優子
    • Journal Title

      電気泳動

      Volume: 65

    • NAID

      130008072916

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Forelimb movements evoked by optogenetic stimulation of the macaque motor cortex2020

    • Author(s)
      Watanabe H, Sano H, Chiken S, Kobayashi K, Fukata Y, Fukata M, Mushiake H, Nambu A
    • Journal Title

      Nat Commun

      Volume: 11 Issue: 1 Pages: 3253-3253

    • DOI

      10.1038/s41467-020-16883-5

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A genetically encoded red fluorescence dopamine biosensor enables dual imaging of dopamine and norepinephrine2020

    • Author(s)
      Nakamoto Chihiro、Goto Yuhei、Tomizawa Yoko、Fukata Yuko、Fukata Masaki、Harpsoe Kasper、Gloriam David E.、Aoki Kazuhiro、Takeuchi Tomonori
    • Journal Title

      bioRxiv

      Volume: -

    • DOI

      10.1101/2020.05.25.115162

    • Related Report
      2020 Research-status Report
    • Open Access / Int'l Joint Research
  • [Journal Article] The extracellular domain of angulin-1 and palmitoylation of its cytoplasmic region are required for angulin-1 assembly at tricellular contacts2020

    • Author(s)
      Yukako Oda, Taichi Sugawara, Yuko Fukata, Yasushi Izumi, Tetsuhisa Otani, Tomohito Higashi, Masaki Fukata, Mikio Furuse
    • Journal Title

      Journal of Biological Chemistry

      Volume: 295 Issue: 13 Pages: 4289-4302

    • DOI

      10.1074/jbc.ra119.010491

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability2020

    • Author(s)
      Kornau Hans‐Christian、Kreye Jakob、Stumpf Alexander、Fukata Yuko、Parthier Daniel、Sammons Rosanna P.、Imbrosci Barbara、Kurpjuweit Sarah、Kowski Alexander B.、Fukata Masaki、Pruss Harald、Schmitz Dietmar
    • Journal Title

      Annals of Neurology

      Volume: 87 Issue: 3 Pages: 405-418

    • DOI

      10.1002/ana.25666

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP62019

    • Author(s)
      Sada Ryota、Kimura Hirokazu、Fukata Yuko、Fukata Masaki、Yamamoto Hideki、Kikuchi Akira
    • Journal Title

      Science Signaling

      Volume: 12 Issue: 608 Pages: 9519-9519

    • DOI

      10.1126/scisignal.aat9519

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ABHD10 is an S-depalmitoylase affecting redox homeostasis through peroxiredoxin-52019

    • Author(s)
      Cao Yang、Qiu Tian、Kathayat Rahul S.、Azizi Saara-Anne、Thorne Anneke K.、Ahn Daniel、Fukata Yuko、Fukata Masaki、Rice Phoebe A.、Dickinson Bryan C.
    • Journal Title

      Nature Chemical Biology

      Volume: 15 Issue: 12 Pages: 1232-1240

    • DOI

      10.1038/s41589-019-0399-y

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Targeting CCR5 trafficking to inhibit HIV-1 infection2019

    • Author(s)
      Boncompain Gaelle、Herit Floriane、Tessier Sarah、Lescure Aurianne、Del Nery Elaine、Gestraud Pierre、Staropoli Isabelle、Fukata Yuko、Fukata Masaki、Brelot Anne、Niedergang Florence、Perez Franck
    • Journal Title

      Science Advances

      Volume: 5 Issue: 10

    • DOI

      10.1126/sciadv.aax0821

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Systematic Screening of Depalmitoylating Enzymes and Evaluation of Their Activities by the Acyl-PEGyl Exchange Gel-Shift (APEGS) Assay2019

    • Author(s)
      Kanadome T, Yokoi N, Fukata Y, Fukata M.
    • Journal Title

      Methods Mol Biol

      Volume: 印刷中 Pages: 83-98

    • DOI

      10.1007/978-1-4939-9532-5_7

    • ISBN
      9781493995318, 9781493995325
    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Limbic Encephalitis in a Cat with Hippocampal Necrosis, putatively associated with DCC (deleted in colorectal cancer; Netrin-1 Receptor) Antibodies2019

    • Author(s)
      Hasegawa D, Ohnishi Y, Koyama E, Matsunaga S, Ohtani S, Nakanishi A, Shiga T, Chambers JK, Uchida K, Yokoi N, Fukata Y, Fukata M.
    • Journal Title

      J Vet Intern Med

      Volume: 印刷中 Issue: 3 Pages: 1440-1445

    • DOI

      10.1111/jvim.15492

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] Trans-synaptic LGI1-ADAM22-MAGUK protein complex in synaptic functions and disorders2021

    • Author(s)
      Fukata Masaki、Fukata Yuko
    • Organizer
      SYNABS Symposium (Germany, Virtual meeting)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Acyl-PEGyl exchange gel-shift (APEGS) assay for palmitoylation quantification2020

    • Author(s)
      Fukata Masaki、Yokoi Norihiko、Fukata Yuko
    • Organizer
      第71回 日本電気泳動学会総会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Synaptic function regulated by palmitate cycling on PSD-95 and trans-synaptic LGI1 and ADAM222020

    • Author(s)
      Fukata Masaki、Yuri Miyazaki、Yokoi Norihiko、Fukata Yuko
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Synapse maturation regulated by palmitate cycling on PSD-95 and trans-synaptic LGI1 and ADAM222019

    • Author(s)
      Fukata Masaki
    • Organizer
      CFC seminar series Spring 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] The LGI1-ADAM22 protein complex in synaptic transmission and synaptic disorders2019

    • Author(s)
      Fukata Masaki
    • Organizer
      2019 Korea-Yonsei-NIPS International Joint Symposium
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] シナプス成熟機構とその破綻による病態機構2019

    • Author(s)
      深田正紀
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Physiological roles of trans-synaptic LGI1-ADAM22-MAGUK complex2019

    • Author(s)
      Fukata Y, Hirano Y, Inahashi H, Miyazaki M, Yokoi N, Sanbo M, Goto T, Hirabayashi M, Fukata M
    • Organizer
      Neuroscience Meeting SfN 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Book] 膜タンパク質工学ハンドブック2020

    • Author(s)
      平野瑶子、宮﨑裕理、横井紀彦、平田哲也、深田正紀、深田優子
    • Total Pages
      17
    • Publisher
      エヌ・ティー・エス
    • ISBN
      9784860435370
    • Related Report
      2020 Research-status Report
  • [Remarks] 研究室ホームページ

    • URL

      https://www.nips.ac.jp/fukata/

    • Related Report
      2021 Annual Research Report 2020 Research-status Report 2019 Research-status Report
  • [Remarks] プレスリリース 新たなてんかん治療戦略を提案

    • URL

      https://www.nips.ac.jp/release/2021/12/_adam22.html

    • Related Report
      2021 Annual Research Report
  • [Remarks] プレスリリース 新たなてんかん治療戦略を提案

    • URL

      https://www.amed.go.jp/news/release_20211215.html

    • Related Report
      2021 Annual Research Report
  • [Remarks] プレスリリース 新規赤色蛍光ドーパミンバイオセンサーの開発

    • URL

      https://www.nibb.ac.jp/press/2021/12/20.html

    • Related Report
      2021 Annual Research Report
  • [Remarks] プレスリリース:神経シナプス間の軸調整を担う分子群を発見―新たなてんかん病態を解明―

    • URL

      https://www.nips.ac.jp/release/2021/01/post_426.html

    • Related Report
      2020 Research-status Report

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Published: 2019-07-04   Modified: 2023-01-30  

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