LGI1を中心とするシナプス蛋白質ネットワークの老化と認知症の分子病態

• Project Area: Prevention of brain protein aging and dementia
• Project/Area Number: 17H05709
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: National Institute for Physiological Sciences
• Principal Investigator: 深田 正紀 生理学研究所, 分子細胞生理研究領域, 教授 (00335027)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000); Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: シナプス伝達 / 認知症 / タンパク質 / AMPA受容体 / LGI1 / ADAM22 / シナプス / 蛋白質 / 脳神経疾患 / 脳・神経 / 生理学 / 痴呆

Outline of Annual Research Achievements

神経シナプスの機能障害は認知症発症の重要な初期病態の一つと考えられている。これまでに、私共は脳の速い興奮性シナプス伝達の大部分を司るAMPA型グルタミン酸受容体の制御機構の解明に取り組み、AMPA受容体制御タンパク質としてLGI1-ADAM22（リガンド-受容体）を見出した。本研究では、これまでの研究をさらに発展させ、LGI1-ADAM22経路の全容とその破綻による病態機構を解明することを目指した。平成30年度は、LGI1-ADAM22のX線結晶構造解析の知見に基づき（東京大学、深井周也博士との共同研究）、LGI1-ADAM22がヘテロ4量体としてシナプス間を架橋することを発表した（Yamagata, Miyazaki et al, Nature Commun, 2018）。また、認知機能障害やけいれん発作、記憶障害を呈する自己免疫性辺縁系脳炎患者の血清や髄液より得たLGI1自己抗体を用いて、神経細胞の過興奮やシナプス伝達異常の原因となる病態機構の一端を明らかにした。これら自己抗体は、nativeのLGI1分子と高い親和性で結合することから、LGI1の詳細な局在解析に使用できると共に、LGI1に相互作用する分子群を網羅的に同定し、LGI1の作用機序を解明する上でも極めて有用であると考えられる。さらに、私共はLGI1およびADAM22の解析のみならず、これら分子が属するファミリー分子群（LGI2, LGI3, LGI4やADAM11、ADAM23）に関しても解析を進めた。このように本研究では、LGI1とADAM22の分子構造基盤を明らかし、LGI1-ADAM22の作用機序と病態機構の解明を推し進めた。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] University of Edinburgh(英国)
• [Int'l Joint Research] University of Chicago/University of California, San Francisco/University of Michigan(米国)
• [Int'l Joint Research] DZNE(ドイツ)
• [Int'l Joint Research] Institute of Science and Technology(オーストリア)
• [Int'l Joint Research] Utrecht University(オランダ)
• [Journal Article] Systematic Screening of Depalmitoylating Enzymes and Evaluation of Their Activities by the Acyl-PEGyl Exchange Gel-Shift (APEGS) Assay (2019)
  • 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
  • Peer Reviewed
• [Journal Article] Limbic Encephalitis in a Cat with Hippocampal Necrosis, putatively associated with DCC (deleted in colorectal cancer; Netrin-1 Receptor) Antibodies (2019)
  • 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
  • Peer Reviewed
• [Journal Article] Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22 (2018)
  • Author(s): Yamagata Atsushi、Miyazaki Yuri、Yokoi Norihiko、Shigematsu Hideki、Sato Yusuke、Goto-Ito Sakurako、Maeda Asami、Goto Teppei、Sanbo Makoto、Hirabayashi Masumi、Shirouzu Mikako、Fukata Yuko、Fukata Masaki、Fukai Shuya
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 1546-1546
  • DOI: 10.1038/s41467-018-03947-w
  • Peer Reviewed / Open Access
• [Journal Article] Long-term clinical follow-up of a patient with non-paraneoplastic cerebellar ataxia associated with anti-mGluR1 autoantibodies (2018)
  • Author(s): Yoshikura Nobuaki、Kimura Akio、Fukata Masaki、Fukata Yuko、Yokoi Norihiko、Harada Naoko、Hayashi Yuichi、Inuzuka Takashi、Shimohata Takayoshi
  • Journal Title: Journal of Neuroimmunology Volume: 319 Pages: 63-67
  • DOI: 10.1016/j.jneuroim.2018.04.001
  • Peer Reviewed
• [Journal Article] Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22 (2018)
  • Author(s): Yamagata A, Miyazaki Y, Yokoi N, Shigematsu H, Sato Y, Goto-Ito S, Maeda A, Goto T, Sanbo M, Hirabayashi M, Shirouzu M, Fukata Y, Fukata M, Fukai S
  • Journal Title: Nat Commun Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Neurobiology of autoimmune encephalitis. (2018)
  • Author(s): Fukata M, Yokoi N, Fukata Y.
  • Journal Title: Curr Opin Neurobiol Volume: 48 Pages: 1-8
  • DOI: 10.1016/j.conb.2017.07.012
  • Peer Reviewed
• [Journal Article] パルミトイル化修飾酵素を軸とした神経機能研究 (2018)
  • Author(s): 平田 哲也，深田 優子，深田 正紀
  • Journal Title: 生化学 Volume: 90
  • NAID: 40021617357
  • Peer Reviewed
• [Journal Article] Dynamic Palmitoylation Targets MAP6 to the Axon to Promote Microtubule Stabilization during Neuronal Polarization (2017)
  • Author(s): Tortosa E, Adolfs Y, Fukata M, Pasterkamp RJ, Kapitein LC, Hoogenraad CC
  • Journal Title: Neuron Volume: 94 Issue: 4 Pages: 809-825
  • DOI: 10.1016/j.neuron.2017.04.042
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Secreted Metalloproteinase ADAMTS-3 Inactivates Reelin (2017)
  • Author(s): Ogino H, Hisanaga A, Kohno T, Kondo Y, Okumura K, Kamei T, Sato T, Asahara H, Tsuiji H, Fukata M, Hattori M
  • Journal Title: J Neurosci Volume: 37 Issue: 12 Pages: 3181-3191
  • DOI: 10.1523/jneurosci.3632-16.2017
  • Peer Reviewed / Open Access
• [Journal Article] In situ screening for postsynaptic cell adhesion molecules during synapse formation. (2017)
  • Author(s): Uemura T, Maeda A, Yasumura M, Shimada T, Fukata Y, Fukata M, Yoshida T
  • Journal Title: Journal of Biochemistry Volume: 印刷中 Pages: 295-302
  • DOI: 10.1093/jb/mvx030
  • NAID: 40021380573
  • Peer Reviewed
• [Journal Article] Coupling of a voltage-gated Ca2+ channel homologue with a plasma membrane H+-ATPase in yeast (2017)
  • Author(s): Cho T, Ishii-Kato A, Fukata Y, Nakayama Y, Iida K, Fukata M, Iida H
  • Journal Title: Genes Cells Volume: 22 Issue: 1 Pages: 94-104
  • DOI: 10.1111/gtc.12458
  • Peer Reviewed / Open Access
• [Journal Article] Epilepsy and synaptic proteins (2017)
  • Author(s): Fukata Y, Fukata M
  • Journal Title: Curr Opin Neurobiol Volume: 45 Pages: 1-8
  • DOI: 10.1016/j.conb.2017.02.001
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Binding mode and physiological role of epilepsy-related ligand/receptor LGI1-ADAM22 complex based on structural analysis (2018)
  • Author(s): Miyazaki Y, Yamagata A, Yokoi N, Fukata Y, Fukai S, Fukata M
  • Organizer: Neuroscience 2018
  • Int'l Joint Research
• [Presentation] Synapse maturation regulated by palmitate cycling on PSD-95 and trans-synaptic LGI1 and ADAM22 (2018)
  • Author(s): Fukata Y, Yokoi N, Hirata T, Miyazaki Y, Hirano Y, Fukata M
  • Organizer: 2018 ASCB | EMBO Annual Meeting
  • Int'l Joint Research
• [Presentation] Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22 (2018)
  • Author(s): Yamagata A, Miyazaki Y, Shigematsu H, Shirouzu M, Fukata Y, Fukata M, Fukai S
  • Organizer: 日本生物物理学会第56回年会
• [Presentation] てんかんの原因となる蛋白質複合体 LGI1-ADAM22 の構造基盤 (2018)
  • Author(s): 山形敦史、 宮崎裕理、深田優子、深田正紀、深井周也
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 抗mGluR1 抗体陽性小脳性運動失調症2症例の臨床像の検討 (2018)
  • Author(s): 吉倉延亮、安井敬三、木村暁夫、横井紀彦、深田優子、深田正紀、下畑享良
  • Organizer: 第30回日本神経免疫学会学術集会
• [Presentation] Pathophysiological role of epilepsy-related LGI1 and ADAM22 in hippocampal synaptic development (2017)
  • Author(s): Masaki Fukata
  • Organizer: Spring Hippocampal Research Conference
  • Int'l Joint Research / Invited
• [Presentation] Local palmitoylation machinery in the postsynaptic nanodomain organization (2017)
  • Author(s): Masaki Fukata
  • Organizer: 5th Annual iGluR Retreat
  • Int'l Joint Research / Invited
• [Presentation] Role of local palmitoylation machinery in the postsynaptic nanodomain organization (2017)
  • Author(s): Masaki Fukata, Norihiko Yokoi, Yuko Fukata
  • Organizer: 13th International congress of the Polish Neuroscience Society
  • Int'l Joint Research / Invited
• [Presentation] 局所パルミトイル化サイクルによるシナプス・ナノドメイン構築 (2017)
  • Author(s): Masaki Fukata
  • Organizer: 2017年度生命科学系学会合同年次大会
  • Invited
• [Remarks] 自然科学研究機構 生理学研究所 生体膜研究部門ホームページ
  • URL: http://www.nips.ac.jp/fukata/
• [Remarks] てんかんの原因タンパク質が神経細胞間の橋渡しをする仕組みを解明
  • URL: http://www.nips.ac.jp/release/2018/04/post_363.html