title: Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy.
abstract: Epilepsy is one of the most common and intractable brain disorders. Mutations in the human gene LGI1, encoding a neuronal secreted protein, cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). However, the pathogenic mechanisms of LGI1 mutations remain unclear. We classified 22 reported LGI1 missense mutations as either secretion defective or secretion competent, and we generated and analyzed two mouse models of ADLTE encoding mutant proteins representative of the two groups. The secretion-defective LGI1(E383A) protein was recognized by the ER quality-control machinery and prematurely degraded, whereas the secretable LGI1(S473L) protein abnormally dimerized and was selectively defective in binding to one of its receptors, ADAM22. Both mutations caused a loss of function, compromising intracellular trafficking or ligand activity of LGI1 and converging on reduced synaptic LGI1-ADAM22 interaction. A chemical corrector, 4-phenylbutyrate (4PBA), restored LGI1(E383A) folding and binding to ADAM22 and ameliorated the increased seizure susceptibility of the LGI1(E383A) model mice. This study establishes LGI1-related epilepsy as a conformational disease and suggests new therapeutic options for human epilepsy.
authors.affiliation: 1] Division of Membrane Physiology, Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan. [2] Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Yokoi
authors.affiliation: 1] Division of Membrane Physiology, Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan. [2] Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fukata
authors.affiliation: Division of Neural Signaling, Department of Information Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kase
authors.affiliation: Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Department of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Martine
authors.initials: M
authors.lastname: Jaegle
authors.affiliation: 1] Division of Membrane Physiology, Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan. [2] Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, Japan.
authors.forename: Toshika
authors.initials: T
authors.lastname: Ohkawa
authors.affiliation: Division of Membrane Physiology, Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Iwanari
authors.affiliation: 1] Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [2] Komaba Open Lab, PeptiDream Incorporation, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Mochizuki
authors.affiliation: Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Hamakubo
authors.affiliation: 1] Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, Japan. [2] Division of Neural Signaling, Department of Information Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Imoto
authors.affiliation: 1] Department of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands. [2] Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK.
authors.forename: Dies
authors.initials: D
authors.lastname: Meijer
authors.affiliation: 1] Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Japan. [2] Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: 1] Division of Membrane Physiology, Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan. [2] Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Fukata
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D017034:Epilepsy, Frontal Lobe / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010654:Phenylbutyrates / Q000008:administration & dosage; D017510:Protein Folding / Q000187:drug effects; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012640:Seizures / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D012893:Sleep Wake Disorders / Q000235:genetics* / Q000473:pathology / Q000628:therapy
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C116499:LGI1 protein, human; D009419:Nerve Tissue Proteins; D010654:Phenylbutyrates; D011506:Proteins; C075773:4-phenylbutyric acid; D051722:ADAM Proteins; C121258:Adam22 protein, mouse