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Insights into the mechanisms of epilepsy from structural biology of LGI1–ADAM22

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Abstract

Epilepsy is one of the most common brain disorders, which can be caused by abnormal synaptic transmissions. Many epilepsy-related mutations have been identified in synaptic ion channels, which are main targets for current antiepileptic drugs. One of the novel potential targets for therapy of epilepsy is a class of non-ion channel-type epilepsy-related proteins. The leucine-rich repeat glioma-inactivated protein 1 (LGI1) is a neuronal secreted protein, and has been extensively studied as a product of a causative gene for autosomal dominant lateral temporal lobe epilepsy (ADLTE; also known as autosomal dominant partial epilepsy with auditory features [ADPEAF]). At least 43 mutations of LGI1 have been found in ADLTE families. Additionally, autoantibodies against LGI1 in limbic encephalitis are associated with amnesia, seizures, and cognitive dysfunction. Although the relationship of LGI1 with synaptic transmission and synaptic disorders has been studied genetically, biochemically, and clinically, the structural mechanism of LGI1 remained largely unknown until recently. In this review, we introduce insights into pathogenic mechanisms of LGI1 from recent structural studies on LGI1 and its receptor, ADAM22. We also discuss the mechanism for pathogenesis of autoantibodies against LGI1, and the potential of chemical correctors as novel drugs for epilepsy, with structural aspects of LGI1–ADAM22.

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Acknowledgements

The research in SF’s lab has been supported by Grants from JSPS/MEXT KAKENHI (JP16H04749 to A.Y. and JP24247014 and JP18H03983 to S.F.) and JST CREST (JPMJCR12M5) to S.F. We apologize to colleagues whose research could not be cited due to space limitation.

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  1. Atsushi Yamagata

    Present address: Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, 230-0045, Japan

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  1. Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, 113-0032, Japan

    Atsushi Yamagata & Shuya Fukai

  2. Synchrotron Radiation Research Organization, The University of Tokyo, Tokyo, 113-0032, Japan

    Atsushi Yamagata & Shuya Fukai

  3. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, 277-8561, Japan

    Atsushi Yamagata & Shuya Fukai

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Yamagata, A., Fukai, S. Insights into the mechanisms of epilepsy from structural biology of LGI1–ADAM22. Cell. Mol. Life Sci. 77, 267–274 (2020). https://doi.org/10.1007/s00018-019-03269-0

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