記憶と脳の安定性を保持するLGI1リガンドの老化と認知症における役割

• Project Area: Prevention of brain protein aging and dementia
• Project/Area Number: 15H01570
• 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): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
• Keywords: シナプス伝達 / 認知症 / 蛋白質 / AMPA受容体 / LGI1 / ADAM22 / ABHD17 / パルミトイル化修飾 / 脳神経疾患 / 脳・神経 / 生理学 / 痴呆

Outline of Annual Research Achievements

認知症の制御には認知症関連蛋白質の発掘は欠かせない。私共は認知症発症の最初期にはシナプス伝達機構の破綻が関与すると考え、AMPA型グルタミン酸受容体を介したシナプス伝達の制御機構に焦点を当てて研究を進めてきた。昨年度は、てんかん関連蛋白質LGI1の欠損が、足場蛋白質PSD-95を介したシナプス伝達制御に必須であることを明らかにした(Lovero、深田ら PNAS 2015)。今年度は、このPSD-95の機能制御を担う新たな分子を探索、同定した（横井、深田ら J Neurosci 2016）。PSD-95は、興奮性シナプスのシナプス後肥厚部（PSD）に濃縮し、AMPA受容体やNMDA受容体、Neuroliginなどを裏打ちし、シナプス伝達やシナプス形成を制御する。PSD-95がPSDに局在するためには、パルミトイル化脂質修飾が必要である。パルミトイル化修飾は可逆反応であり外界刺激に依存して制御される。これまでに私共はPSD-95パルミトイル化酵素としてDHHC2、DHHC3を同定してきたが、脱パルミトイル化酵素に関しては長らく不明であった。今回、私共はPSD-95脱パルミトイル化酵素としてABHD17A、17B、17Cを同定した。そして、ABHD17を海馬神経細胞に過剰発現させると、PSD-95とAMPA受容体のシナプス局在が激減し、樹状突起スパインの数が減少することを見出した。また、これら酵素群をノックダウンするとPSD-95の脱パルミトイル化が有意に阻害されることを見出した。さらに、私共は蛋白質のパルミトイル化状態（ストイキオメトリー）を検出する生化学的手法(APEGS法)を開発した。すなわち、シナプス蛋白質のパルミトイル化状態の変容が脳蛋白質老化の一因になっているかを検討することが可能となる基盤的技術の開発にも成功した。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28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 California, San Francisco(米国)
• [Int'l Joint Research] University of Helsinki(Finland)
• [Int'l Joint Research] DZNE(Germany)
• [Int'l Joint Research] University of California, San Francisco(米国)
• [Int'l Joint Research] University of Helsinki(Finland)
• [Journal Article] Astrocyte-mediated infantile-onset leukoencephalopathy mouse model (2017)
  • Author(s): Sugio S, Tohyama K, Oku S, Fujiyoshi K, Yoshimura T, Hikishima K, Yano R, Fukuda T, Nakamura M, Okano H, Watanabe M1, Fukata M, Ikenaka K, F Tanaka K
  • Journal Title: Glia Volume: 65 Issue: 1 Pages: 150-168
  • DOI: 10.1002/glia.23084
  • Peer Reviewed / Open Access
• [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] 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] The LGI1-ADAM22 protein complex in synaptic transmission and synaptic disorders (2017)
  • Author(s): Fukata Y, Yokoi N, Miyazaki Y, Fukata M
  • Journal Title: Neurosci Res Volume: 116 Pages: 39-45
  • DOI: 10.1016/j.neures.2016.09.011
  • Peer Reviewed / Acknowledgement Compliant
• [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
• [Journal Article] Identification of PSD-95 depalmitoylating enzymes (2016)
  • Author(s): Yokoi N*, Fukata Y*, Sekiya A, Murakami T, Kobayashi K, Fukata M
  • Journal Title: J Neurosci Volume: 36 Issue: 24 Pages: 6431-6444
  • DOI: 10.1523/jneurosci.0419-16.2016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dysfunctional ADAM22 implicated in progressive encephalopathy with cortical atrophy and epilepsy (2016)
  • Author(s): Muona M, Fukata Y, Anttonen AK, Laari A, Palotie A, Pihko H, Lönnqvist T, Valanne L, Somer M, Fukata M, Lehesjoki AE
  • Journal Title: Neurol Genet Volume: 2 Issue: 1
  • DOI: 10.1212/nxg.0000000000000046
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Local palmitoylation cycles and specialized membrane domain organization (2016)
  • Author(s): Fukata Y, Murakami T, Yokoi N, Fukata M
  • Journal Title: Curr Top Membr Volume: 77 Pages: 97-141
  • DOI: 10.1016/bs.ctm.2015.10.003
  • Peer Reviewed
• [Journal Article] The LGI1-ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function (2015)
  • Author(s): Lovero KL, Fukata Y, Grangera AJ, Fukata M, Nicoll RA
  • Journal Title: Proc Natl Acad Sci USA Volume: 112 Issue: 30
  • DOI: 10.1073/pnas.1511910112
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Synaptic nanodomains generated by local palmitoylation cycles (2015)
  • Author(s): Masaki Fukata, Atsushi Sekiya, Tatsuro Murakami, Norihiko Yokoi, Yuko Fukata
  • Journal Title: Biochemical Society Transactions Volume: 43(2) Issue: 2 Pages: 199-204
  • DOI: 10.1042/bst20140238
  • Peer Reviewed
• [Journal Article] ELMOD2 is anchored to lipid droplets by palmitoylation and regulates ATGL recruitment (2015)
  • Author(s): Michitaka Suzuki, Tatsuro Murakami, Jinglei Cheng, Hiroyuki Kano, Masaki Fukata, and Toyoshi Fujimoto
  • Journal Title: MOLECULAR BIOLOGY OF THE CELL Volume: - Issue: 12 Pages: 2333-2342
  • DOI: 10.1091/mbc.e14-11-1504
  • Peer Reviewed / Open Access
• [Journal Article] The BAI1 regulates spatial learning and synaptic plasticity in the hippocampus. (2015)
  • Author(s): Dan Zhu, Chenchen Li, Andrew M. Swanson, Rosa M. Villalba, Jidong Guo, Zhaobin Zhang, Shannon Matheny, Tatsuro Murakami, Jason R. Stephenson, Sarah Daniel, Masaki Fukata, Randy A. Hall, Jeffrey J. Olson, Gretchen N. Neigh, Yoland Smith, Donald G. Rainnie, and Erwin G. Van Meir.
  • Journal Title: Journal of Clinical Investigation Volume: 125(4) Issue: 4 Pages: 1497-1508
  • DOI: 10.1172/jci74603
  • Peer Reviewed / Open Access
• [Presentation] Regulatory mechanisms for AMPA receptors through PSD-95 (2016)
  • Author(s): Masaki Fukata
  • Organizer: The 47th NIPS International Symposium “Decoding Synapses”
  • Place of Presentation: 岡崎コンファレンスセンター、岡崎市、愛知県
  • Year and Date: 2016-10-26
  • Int'l Joint Research
• [Presentation] Regulators of glutamate receptors and epilepsy (2016)
  • Author(s): Masaki Fukata
  • Organizer: 第50回日本てんかん学会学術集会
  • Place of Presentation: グランシップ、静岡市、静岡県
  • Year and Date: 2016-10-07
  • Invited
• [Presentation] Postsynaptic nanodomains regulated by local palmitoylation machinery (2016)
  • Author(s): Masaki Fukata, Norihiko Yokoi, Atsushi Sekiya, Tatsuro Murakami, Kenta Kobayashi, Yuko Fukata
  • Organizer: 10th Forum of Neuroscience (FENS)
  • Place of Presentation: Bella Center, Copenhagen, Denmark
  • Year and Date: 2016-07-02
  • Int'l Joint Research / Invited
• [Presentation] Molecular mechanisms of PSD95 (de)palmitoylation (2016)
  • Author(s): Masaki Fukata
  • Organizer: Invited Lecture at Medizinische Hochschule Hannover
  • Place of Presentation: Hannover, Germany
  • Invited
• [Presentation] Postsynaptic nanodomains regulated by local palmitoylation machinery (2016)
  • Author(s): Masaki Fukata
  • Organizer: Invited Lecture at Deutsches Zentrum fur Neurodegenerative Erkrankungen (DZNE)
  • Place of Presentation: Magdeburg, Germany
  • Invited
• [Presentation] The LGI1-ADAM22 protein complex in synaptic transmission and disorders (2016)
  • Author(s): Masaki Fukata
  • Organizer: Brain protein aging and dementia control: International workshop 2016
  • Place of Presentation: 名古屋大学医学部鶴友会館、名古屋市、愛知県
  • Int'l Joint Research / Invited
• [Presentation] Postsynaptic nanodomain regulated by PSD-95 palmitoylation machinery (2015)
  • Author(s): Masaki Fukata
  • Organizer: Pacifichem 2015
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 2015-12-15
  • Int'l Joint Research / Invited
• [Presentation] Local palmitoylation cycles organize postsynaptic nanodomains (2015)
  • Author(s): Masaki Fukata
  • Organizer: 第38回日本分子生物学会年会/第88回日本生化学会大会
  • Place of Presentation: 神戸国際会議場・展示場（兵庫県神戸市中央区）
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] Molecular pathogenic mechanisms of epilepsy caused by LGI1 mutations (2015)
  • Author(s): Norihiko Yokoi, Yuko Fukata, Daisuke Kase, Taisuke Miyazaki, Martin Jaegle, Keiji Imoto, Deis Meijer, Masahiko Watanabe, Masaki Fukata
  • Organizer: 45th annual meeting of the Society for Neuroscience
  • Place of Presentation: McCormick Place, Chicago, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Exploration of depalmitoylating enzymes regulating bi-directional trafficking of small GTPase HRas (2015)
  • Author(s): Tatsuro Murakami, Atsushi Sekiya, Yuko Fukata, Masaki Fukata
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場・展示場（兵庫県神戸市中央区）
  • Year and Date: 2015-07-28
• [Presentation] Role of LGI1-ADAM22 in synaptic function and disorders (2015)
  • Author(s): Masaki Fukata
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場・展示場（兵庫県神戸市中央区）
  • Year and Date: 2015-07-28
  • Invited
• [Presentation] Regulatory mechanism for local palmitoylation cycles on PSD-95 (2015)
  • Author(s): Masaki Fukata
  • Organizer: FASEB Science Research Conference “Protein Lipidation, Signaling, and Membrane Domains”
  • Place of Presentation: Saxtons River, Vermont, USA
  • Year and Date: 2015-07-19
  • Int'l Joint Research / Invited
• [Presentation] Postsynaptic nanodomains organized by local palmitoylation machinery (2015)
  • Author(s): Yuko Fukata, Atsushi Sekiya, Tatsuro Murakami, Norihiko Yokoi, Kenta Kobayashi, Masaki Fukata
  • Organizer: FASEB Science Research Conference “Protein lipidation, Signaling, and Membrane Domains”
  • Place of Presentation: Saxtons River, Vermont, USA
  • Year and Date: 2015-07-19
  • Int'l Joint Research
• [Presentation] Stoichiometric analysis of palmitoylation cycles on PSD-95 (2015)
  • Author(s): Norihiko Yokoi, Atsushi Sekiya, Tatsuro Murakami, Yuko Fukata, Masaki Fukata
  • Organizer: FASEB Science Research Conference “Protein lipidation, Signaling, and Membrane Domains”
  • Place of Presentation: Saxtons River, Vermont, USA
  • Year and Date: 2015-07-19
  • Int'l Joint Research
• [Presentation] Characterization of a mouse model with genetic deletion of DHHC2 palmitoyl acyl transferase (2015)
  • Author(s): Tatsuro Murakami, Atsushi Sekiya, Manabu Abe, Kenji Sakimura, Yuko Fukata, Masaki Fukata
  • Organizer: FASEB Science Research Conference “Protein lipidation, Signaling, and Membrane Domains”
  • Place of Presentation: Saxtons River, Vermont, USA
  • Year and Date: 2015-07-19
  • Int'l Joint Research
• [Presentation] Postsynaptic nanodomains organized by PSD-95 palmitoylation machinery (2015)
  • Author(s): Masaki Fukata
  • Organizer: 第67回日本細胞生物学会大会
  • Place of Presentation: タワーホール船堀（東京都江戸川区）
  • Year and Date: 2015-06-30
  • Invited
• [Book] メンブレントラフィック (2016)
  • Author(s): 深田優子、横井紀彦、宮崎裕理、深田正紀
  • Publisher: 化学同人
• [Book] 細胞工学 (2015)
  • Author(s): 横井紀彦、深田正紀、深田優子
  • Publisher: 秀潤社
• [Remarks] シナプス蛋白質PSD-95の局在を調節する酵素の同定
  • URL: http://www.nips.ac.jp/nips_research/2016/06/psd-95.html
• [Remarks] 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/