Physiological role of the novel neuromodulator "LGI family"

2011 Fiscal Year Final Research Report

• Project/Area Number: 21680029
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Neuroscience in general
• Research Institution: National Institute for Physiological Sciences
• Principal Investigator: FUKATA Yuko 生理学研究所, 細胞器官研究系, 准教授 (40416186)
• Project Period (FY): 2009 – 2011
• Keywords: 神経科学 / リガンド・受容体 / シナプス伝達 / シナプス / グルタミン酸受容体 / AMPA受容体 / LGI1 / 生化学

Research Abstract

Regulatory mechanisms for synaptic transmission should lead to understanding the etiology of brain disorders, such as epilepsy and dementia. So far, we have identified epilepsy-related LGI1 and ADAM22 as the novel ligand/receptor, and showed LGI1 enhances AMPA receptor-mediated synaptic transmission through ADAM22(Fukata et al, Science 2010). To clarify the physiological role of LGI family proteins especially in brain functions, we generated LGI1 knockout(KO) mice and found that LGI1 KO mice showed lethal epileptic phenotype(Fukata et al, PNAS 2010). We found that LGI3 did not bind to ADAM22 and could not rescue LGI1 KO mice, under the condition in which neuronal LGI1 expression could rescue it. Interestingly, LGI4 bound to ADAM22 and partly rescued the epilepsy of LGI1 KO mice. In addition, LGI2 truncation causes a remitting focal epilepsy in dogs(Seppala et al, PLoS Genet 2011). Thus, we found that LGI1, 2, and 4 share their receptors ADAM22 and 23 and regulate the neuronal excitability in different brain regions, while LGI3 may differently function in the brain through the unidentified receptor. Thus, we have made steady and continual progress on clarifying the patho-physiological roles of LGI family in vivo.

Research Products

• [Journal Article] LGI2 Truncation Causes a Remitting Focal Epilepsy in Dogs (2011)
  • Author(s): Seppala EH, Jokinen TS, Fukata M, Fukata Y, Webster MT, Karlsson EK, Kilpinen SK, Steffen F, Dietschi E, Leeb T, Eklund R, Zhao X, Rilstone JJ, Lindblad-Toh K, Minassian BA, Lohi H
  • Journal Title: PLoS Genetics Volume: 7 Pages: e1002194
  • Peer Reviewed
• [Journal Article] Subcellular Golgi localization of Stathmin family proteins is promoted by a specific set of DHHC palmitoyl transferases (2011)
  • Author(s): Levy AD, Devignot V, Fukata Y, Fukata M, Sobel A, Chauvin S
  • Journal Title: Mol Biol Cell Volume: 22 Pages: 1930-1942
  • Peer Reviewed
• [Journal Article] Protein palmitoylation in neuronal development and synaptic plasticity (2010)
  • Author(s): Fukata Y, Fukata M
  • Journal Title: Nat Rev Neurosci Volume: 11 Pages: 161-175
  • Peer Reviewed
• [Journal Article] Ndel1 palmitoylation : a new mean to regulate cytoplasmic dynein activity (2010)
  • Author(s): Shmueli A, Segal M, Sapir T, Tsutsumi R, Noritake J, Bar A, Sapoznik S, Fukata Y, Orr I, Fukata M, Reiner O
  • Journal Title: EMBO J Volume: 29 Pages: 107-119
  • Peer Reviewed
• [Journal Article] Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy (2010)
  • Author(s): Fukata Y, Lovero KL, Iwanaga T, Watanabe A, Yokoi N, Tabuchi K, Shigemoto R, Nicoll RA, Fukata M
  • Journal Title: Proc Natl Acad Sci USA Volume: 107 Pages: 3799-3804
  • Peer Reviewed
• [Journal Article] Mobile DHHC palmitoylating enzyme mediates activity-sensitive synaptic targeting of PSD-95 (2009)
  • Author(s): Noritake J, Fukata Y, Iwanaga T, Hosomi N, Tsutsumi R, Matsuda N, Tani H, Iwanari H, Mochizuki Y, Kodama T, Matsuura Y, Bredt DS, Hamakubo T, Fukata M
  • Journal Title: J Cell Biol Volume: 186 Pages: 147-160
  • Peer Reviewed
• [Journal Article] Identification of G-protein alpha subunit palmitoylating enzyme (2009)
  • Author(s): Tsutsumi R, Fukata Y, Noritake J, Iwanaga T, Perez F Fukata M
  • Journal Title: Mol Cell Biol Volume: 29 Pages: 435-447
  • Peer Reviewed
• [Journal Article] Palmitoylation Regulates Epidermal Homeostasis and Hair Follicle Differentiation (2009)
  • Author(s): Mill P, Lee AWS, Fukata Y, Tsutsumi R, Fukata M, Keighren M, Porter RM, McKie L, Smyth I, Jackson IJ
  • Journal Title: PLoS Genetics Volume: 11 Pages: e1000748
  • Peer Reviewed
• [Journal Article] The Hydrophobic cysteine-rich domain of SNAP25 couples with downstream residues to mediated membrane interactions and recognitions by DHHC palmitoyl transferases (2009)
  • Author(s): Greaves J, Prescott GR, Fukata Y, Fukata M, Salaun C, Chamberlain LH
  • Journal Title: Mol Biol Cell Volume: 20 Pages: 1845-1854
  • Peer Reviewed
• [Journal Article] Differential activity-dependent secretion of brain-derived neurotrophic factor from axon and dendrite (2009)
  • Author(s): Matsuda N, Lu H, Fukata Y, Noritake J, Gao H, Mukherjee S, Nemoto T, Fukata M, Poo MM
  • Journal Title: J Neurosci Volume: 29 Pages: 14185-14198
  • Peer Reviewed
• [Journal Article] Dynamic protein palmitoylation in cellular signaling (2009)
  • Author(s): Iwanaga T, Tsutsumi R, Noritake J, Fukata Y, Fukata M
  • Journal Title: Prog Lipid Res Volume: 48 Pages: 117-127
  • Peer Reviewed
• [Journal Article] Leucine-rich glioma inactivated 1(Lgi1), an epilepsy-related secreted protein, has a nuclear localization signal and localizes both to the cytoplasm and nucleus of the caudal ganglionic eminence neurons.
  • Author(s): Kusuzawa S, Honda H, Fukata Y, Masaki Fukata M, Kanatani S, Tanaka DH, Nakajima K
  • Journal Title: Eur J Neurosci Volume: (in press)
  • Peer Reviewed
• [Journal Article] Synaptic plasticity regulated by protein-protein interactions and posttranslational modifications
  • Author(s): Yokoi N, Fukata M, Fukata Y
  • Journal Title: International Review of Cell & Molecular Biology Volume: (in press)
• [Journal Article] DHHC proteins
  • Author(s): Oku S, Fukata Y, Fukata M
  • Journal Title: Encyclopedia of Signaling Molecules Volume: (in press)
• [Presentation] Molecular dissection of epilepsy-related neuronal secreted protein (2011)
  • Author(s): Fukata Y, Yokoi N, Ohkawa T, Fukata M
  • Organizer: LGI 1.51st Annual Meeting of American Society for Cell Biology
  • Place of Presentation: Denver, U.S.A
  • Year and Date: 20111203-1207
• [Presentation] Visualization of endogenous palmitoylated PSD-95 reveals local palmitoyltransferase-induced nucleation of postsynaptic assembly (2011)
  • Author(s): Fukata Y, Dimitrov A, Noritake J, Vielemeyer O, Perez F, Fukata M
  • Organizer: 41st Annual Meeting of Society for Neuroscience
  • Place of Presentation: Washington DC, U.S.A
  • Year and Date: 20111112-16
• [Presentation] Possible involvement of epilepsy-related ligand/receptors, LGI1/ADAM22/ADAM23 in trans-synaptic interaction (2010)
  • Author(s): Fukata Y, Lovero KL, Iwanaga T, Yokoi N, Nicoll RA, Fukata M
  • Organizer: Gordon Research Conferences "Cell Biology of the Neuron"
  • Place of Presentation: Waterville Valley, U.S.A
  • Year and Date: 20100627-0702
• [Presentation] Invited Role of the novel epilepsy-related protein network in synaptic transmission (2009)
  • Author(s): Fukata Y
  • Organizer: Japan-Taiwan Joint Symposium on Cell Signaling and Gene Regulation
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20091111-12
• [Presentation] In vivo function of epilepsy-related ligand LGI1 (2009)
  • Author(s): Fukata Y, Watanabe A, Iwanaga T, Fukata M
  • Organizer: 36th International Congress of Physiological Sciences
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20090727-0801
• [Book] 細胞工学 (2010)
  • Author(s): 岩永剛、深田正紀、深田優子
  • Total Pages: 594-595
  • Publisher: 学研メディカル秀潤社
• [Book] Medical Bio (2010)
  • Author(s): 横井紀彦、深田正紀、深田優子
  • Total Pages: 40-47
  • Publisher: オーム社
• [Remarks]
  • URL: http://www.nips.ac.jp/fukata/