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Nat Med. 2015 Jan;21(1):19-26. doi: 10.1038/nm.3759. Epub 2014 Dec 8.

Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy.

Author information

1
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.
2
Division of Neural Signaling, Department of Information Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan.
3
Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
4
Department of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
5
Division of Membrane Physiology, Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan.
6
Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
7
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.
8
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.
9
1] Department of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands. [2] Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK.
10
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.

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.

PMID:
25485908
DOI:
10.1038/nm.3759
[Indexed for MEDLINE]

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