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

Yamagata, Atsushi; Fukai, Shuya

doi:10.1007/s00018-019-03269-0

Cited by 35 publications

(36 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This 3:3 assembly mode may act in a cis-fashion and cluster Kv 1 channels, for example, at the axon initial segment where LGI1-ADAM22-PSD-93/95 localizes (SI Appendix, Fig. S2D) (44). Collectively, we suggest that the LGI1-ADAM22 complex has three distinct but not mutually exclusive functions toward MAGUKs, depending on the following subcellular contexts: 1) to align pre-and postsynaptic MAGUKs as a hub in transsynaptic nanocolumns, 2) to locally condense MAGUKs as an extracellular scaffold, and 3) to activate the MAGUK's scaffolding activity as a PDZ ligand.…”

Section: Discussionmentioning

confidence: 99%

LGI1–ADAM22–MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention

Fukata

Chen

Chiken

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Physiological functioning and homeostasis of the brain rely on finely tuned synaptic transmission, which involves nanoscale alignment between presynaptic neurotransmitter-release machinery and postsynaptic receptors. However, the molecular identity and physiological significance of transsynaptic nanoalignment remain incompletely understood. Here, we report that epilepsy gene products, a secreted protein LGI1 and its receptor ADAM22, govern transsynaptic nanoalignment to prevent epilepsy. We found that LGI1–ADAM22 instructs PSD-95 family membrane-associated guanylate kinases (MAGUKs) to organize transsynaptic protein networks, including NMDA/AMPA receptors, Kv1 channels, and LRRTM4–Neurexin adhesion molecules. Adam22ΔC5/ΔC5 knock-in mice devoid of the ADAM22–MAGUK interaction display lethal epilepsy of hippocampal origin, representing the mouse model for ADAM22-related epileptic encephalopathy. This model shows less-condensed PSD-95 nanodomains, disordered transsynaptic nanoalignment, and decreased excitatory synaptic transmission in the hippocampus. Strikingly, without ADAM22 binding, PSD-95 cannot potentiate AMPA receptor-mediated synaptic transmission. Furthermore, forced coexpression of ADAM22 and PSD-95 reconstitutes nano-condensates in nonneuronal cells. Collectively, this study reveals LGI1–ADAM22–MAGUK as an essential component of transsynaptic nanoarchitecture for precise synaptic transmission and epilepsy prevention.

show abstract

Section: Discussionmentioning

confidence: 99%

LGI1–ADAM22–MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention

Fukata

Chen

Chiken

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The released neurotransmitter transfers information from one cell to an adjacent cell, which is required for communication between neurons ( 28 ). A recent study showed that synaptic transmission plays a role in the pathogenesis of neurological diseases such as epilepsy, and its chemical modulators may become potential therapeutic targets ( 29 ). Transsynaptic signals between the pre- and postsynapse are essential for synapse assembly.…”

Section: Discussionmentioning

confidence: 99%

Identification of Core Genes and Screening of Potential Targets in Glioblastoma Multiforme by Integrated Bioinformatic Analysis

Yang

2021

Front. Oncol.

View full text Add to dashboard Cite

Glioblastoma multiforme is the most common primary intracranial malignancy, but its etiology and pathogenesis are still unclear. With the deepening of human genome research, the research of glioma subtype screening based on core molecules has become more in-depth. In the present study, we screened out differentially expressed genes (DEGs) through reanalyzing the glioblastoma multiforme (GBM) datasets GSE90598 from the Gene Expression Omnibus (GEO), the GBM dataset TCGA-GBM and the low-grade glioma (LGG) dataset TCGA-LGG from the Cancer Genome Atlas (TCGA). A total of 150 intersecting DEGs were found, of which 48 were upregulated and 102 were downregulated. These DEGs from GSE90598 dataset were enriched using the overrepresentation method, and multiple enriched gene ontology (GO) function terms were significantly correlated with neural cell signal transduction. DEGs between GBM and LGG were analyzed by gene set enrichment analysis (GSEA), and the significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in synapse signaling and oxytocin signaling pathways. Then, a protein-protein interaction (PPI) network was constructed to assess the interaction of proteins encoded by the DEGs. MCODE identified 2 modules from the PPI network. The 11 genes with the highest degrees in module 1 were designated as core molecules, namely, GABRD, KCNC1, KCNA1, SYT1, CACNG3, OPALIN, CD163, HPCAL4, ANK3, KIF5A, and MS4A6A, which were mainly enriched in ionic signaling-related pathways. Survival analysis of the GSE83300 dataset verified the significant relationship between expression levels of the 11 core genes and survival. Finally, the core molecules of GBM and the DrugBank database were assessed by a hypergeometric test to identify 10 drugs included tetrachlorodecaoxide related to cancer and neuropsychiatric diseases. Further studies are required to explore these core genes for their potentiality in diagnosis, prognosis, and targeted therapy and explain the relationship among ionic signaling-related pathways, neuropsychiatric diseases and neurological tumors.

show abstract

“…LGI1 is a protein secreted by neurons that forms a trans‐synaptic protein complex with binding to presynaptic a disintegrin and metalloproteinase domain‐containing protein 23 (ADAM23) and postsynaptic a disintegrin and metallopeptidase domain 22 (ADAM22). These interactions are important for presynaptic potassium channel (Kv1 subunit) and postsynaptic α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazoleproprionic acid receptor (AMPAR) localization and function, which are important for fast excitatory synaptic transmission and hippocampal long‐term synaptic plasticity 17,90,91 . In rodent antibody‐transfer studies, anti‐LGI1 antibodies prevent LGI1‐ADAM22/23 interactions, which in turn reversibly reduces the levels of presynaptic Kv1.1 channels leading to increased glutamatergic activity 92 and neuronal hyperexcitability.…”

Section: Autoimmune Encephalitidesmentioning

confidence: 99%

“…These interactions are important for presynaptic potassium channel (Kv1 subunit) and postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPAR) localization and function, which are important for fast excitatory synaptic transmission and hippocampal long-term synaptic plasticity. 17,90,91 In rodent antibody-transfer studies, anti-LGI1 antibodies prevent LGI1-ADAM22/23 interactions, which in turn reversibly reduces the levels of presynaptic Kv1.1 channels leading to increased glutamatergic activity 92 and neuronal hyperexcitability. In addition, there is subsequent reduction in postsynaptic AMPARs, 46,92,93 which are present on excitatory and inhibitory neurons.…”

Section: T a B L E 1 (Continued)mentioning

confidence: 99%

Inflammation, ictogenesis, and epileptogenesis: An exploration through human disease

et al. 2020

View full text Add to dashboard Cite

Epilepsy is seen historically as a disease of aberrant neuronal signaling manifesting as seizures. With the discovery of numerous auto‐antibodies and the subsequent growth in understanding of autoimmune encephalitis, there has been an increasing emphasis on the contribution of the innate and adaptive immune system to ictogenesis and epileptogenesis. Pathogenic antibodies, complement activation, CD8+ cytotoxic T cells, and microglial activation are seen, to various degrees, in different seizure‐associated neuroinflammatory and autoimmune conditions. These aberrant immune responses are thought to cause disruptions in neuronal signaling, generation of acute symptomatic seizures, and, in some cases, the development of long‐term autoimmune epilepsy. Although early treatment with immunomodulatory therapies improves outcomes in autoimmune encephalitides and autoimmune epilepsies, patient identification and treatment selection are not always clear‐cut. This review examines the role of the different components of the immune system in various forms of seizure disorders including autoimmune encephalitis, autoimmune epilepsy, Rasmussen encephalitis, febrile infection–related epilepsy syndrome (FIRES), and new‐onset refractory status epilepticus (NORSE). In particular, the pathophysiology and unique cytokine profiles seen in these disorders and their links with diagnosis, prognosis, and treatment decision‐making are discussed.

show abstract

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

Cited by 35 publications

References 56 publications

LGI1–ADAM22–MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention

LGI1–ADAM22–MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention

Identification of Core Genes and Screening of Potential Targets in Glioblastoma Multiforme by Integrated Bioinformatic Analysis

Inflammation, ictogenesis, and epileptogenesis: An exploration through human disease

Contact Info

Product

Resources

About