Studies on excitatory synaptic transmission regulated by neuronal ligand/receptor interactions

• Project/Area Number: 25890021
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: National Institute for Physiological Sciences
• Principal Investigator: NORIHIKO Yokoi 生理学研究所, 細胞器官研究系, 特任助教 (50710969)
• Project Period (FY): 2013-08-30 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: てんかん / ケミカルシャペロン / シナプス伝達 / タンパク質構造病 / タンパク質複合体 / モデルマウス / 治療薬 / 辺縁系脳炎 / AMPA受容体 / PSD-95 / シナプス / 構造病 / 分泌蛋白質 / 変異体 / 蛋白質複合体

Outline of Final Research Achievements

LGI1 is a neuronal secreted protein, and its mutations cause an inherited form of human epilepsy, autosomal dominant lateral temporal lobe epilepsy (ADLTE). However, the patho-physiological functions of LGI1 still remain unclear. Here, we classified 22 reported LGI1 missense ADLTE mutations as either secretion defective or secretion competent, and we generated and analyzed two mouse models of ADLTE expressing the mutant protein representative of the two groups. Both mutations reduced synaptic LGI1-ADAM22 interaction by protein conformational defects in the mouse brain. A chemical chaperone, 4-phenylbutyrate, restored the folding of the secretion-deficient LGI1 mutant and its binding to ADAM22 and ameliorated the increased seizure susceptibility of the LGI1 mutant mice. This study establishes an essential role of the LGI1-ADAM22 interaction to regulate the brain excitability (Yokoi et al. Nat. Med. 2015, 21,19-26).

Research Products

• [Journal Article] Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial temporal lobe epilepsy. (2015)
  • Author(s): Yokoi N, Fukata Y, Kase D, Miyazaki T, Jaegle M, Ohkawa T, Takahashi N, Iwanari H, Mochizuki Y, Hamakubo T, Imoto K, Meijer D, Watanabe M, Fukata M
  • Journal Title: Nat Med Volume: 21 Issue: 1 Pages: 19-26
  • DOI: 10.1038/nm.3759
  • Peer Reviewed / 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] Identification and characterization of GABAA receptor autoantibodies in autoimmune encephalitis (2014)
  • Author(s): Ohkawa T, Satake S, Yokoi N, Miyazaki Y, Ohshita T, Sobue G, Takashima H, Watanabe O, *Fukata Y, *Fukata M (*corresponding author).
  • Journal Title: J Neurosci Volume: 34 Issue: 24 Pages: 8151-8163
  • DOI: 10.1523/jneurosci.4415-13.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Antibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. (2013)
  • Author(s): Ohkawa T, Fukata Y, Yamasaki M, Miyazaki T, Yokoi N, Takashima H, Watanabe M, Watanabe O, Fukata M
  • Journal Title: J Neurosci, Volume: 33 Issue: 46 Pages: 18161-18174
  • DOI: 10.1523/jneurosci.3506-13.2013
  • Peer Reviewed
• [Presentation] A chemical chaperone corrects an LGI1 mutant protein and ameliorates seizure phenotypes in a mouse model of human epilepsy (2015)
  • Author(s): 横井紀彦、深田優子、加勢大輔、宮崎太輔、Martine Jaegle、井本敬二、Dies Meijer、渡辺雅彦、深田正紀
  • Organizer: 第7回NAGOYA グローバルリトリート
  • Place of Presentation: あいち健康プラザ、愛知県
  • Year and Date: 2015-02-13 – 2015-02-14
• [Presentation] Chemical Correction of Missense LGI1 Functions Ameliorates Seizure Phenotype in a Mouse Model of Human Epilepsy (2014)
  • Author(s): 横井紀彦、深田優子、加勢大輔、宮崎太輔、Martine Jaegle、井本敬二、Dies Meijer、渡辺雅彦、深田正紀
  • Organizer: 第3回 NINS colloquium
  • Place of Presentation: ザ・プリンス箱根、神奈川県
  • Year and Date: 2014-12-01 – 2014-12-03
• [Presentation] Chemical Correction of Missense LGI1 Functions Ameliorates Seizure Phenotype in a Mouse Model of Human Epilepsy (2014)
  • Author(s): 横井紀彦、深田優子、加勢大輔、宮崎太輔、Martine Jaegle、井本敬二、Dies Meijer、渡辺雅彦、深田正紀
  • Organizer: 第4回生理研・名大合同シンポジウム
  • Place of Presentation: 名古屋大学、愛知県
  • Year and Date: 2014-11-22
• [Presentation] Molecular mechanisms for LGI1 mutation-related epilepsy and new strategy for human epilepsy (2014)
  • Author(s): Norihiko Yokoi, Yuko Fukata, Daisuke Kase, Taisuke Miyazaki, Martine Jaegle, Keiji Imoto, Dies Meijer, Masahiko Watanabe, Masaki Fukata
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: パシフィコ横浜、神奈川県
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Pathogenic mechanism of epilepsy-related LGI1 mutations in vivo (2013)
  • Author(s): Norihiko Yokoi, Yuko Fukata, Daisuke Kase, Taisuke Miyazaki, Martine Jaegle, Toshika Ohkawa, Keiji Imoto, Dies Meijer, Masahiko Watanabe, Masaki Fukata
  • Organizer: The 3rd NIPS-CIN Joint Symposium
  • Place of Presentation: 愛知県岡崎市 生理学研究所
• [Presentation] Molecular pathogenic mechanisms of epilepsy caused by LGI1 mutations (2013)
  • Author(s): Norihiko Yokoi, Yuko Fukata, Daisuke Kase, Taisuke Miyazaki, Martine Jaegle, Keiji Imoto, Dies Meijer, Masahiko Watanabe, Masaki Fukata
  • Organizer: 43rd annual meeting of the Society for Neuroscience
  • Place of Presentation: Convention center, San Diego, CA, USA
• [Remarks] タンパク質の異常構造を修復することによりてんかんを軽減
  • URL: http://www.nips.ac.jp/release/2014/12/post_285.html
• [Remarks] けいれん・記憶障害をきたす自己免疫性辺縁系脳炎の病態を解明
  • URL: http://www.nips.ac.jp/contents/release/entry/2013/11/-lgi1.html