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

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Significance

This study addresses a fundamental question in neuroscience, namely how does the presynaptic component of the synapse precisely align with the postsynaptic component? This is essential for the proper transmission of signals across the synapse. This paper focuses on a set of transsynaptic, epilepsy-related proteins that are essential for this alignment. We show that the LGI1–ADAM22–MAGUK complex is a key player in the nanoarchitecture of the synapse, such that the release site is directly apposed to the nanocluster of glutamate receptors.

Abstract

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, Kv ₁ channels, and LRRTM4–Neurexin adhesion molecules. Adam22 ^ΔC5/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.

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Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia

Sarosh R. Irani, Sian Alexander, Patrick Waters … (2010)

Antibodies that immunoprecipitate 125I-α-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan’s syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with 125I-α-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan’s syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.

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AMPARs and synaptic plasticity: the last 25 years.

Richard Huganir, Roger A Nicoll (2013)

The study of synaptic plasticity and specifically LTP and LTD is one of the most active areas of research in neuroscience. In the last 25 years we have come a long way in our understanding of the mechanisms underlying synaptic plasticity. In 1988, AMPA and NMDA receptors were not even molecularly identified and we only had a simple model of the minimal requirements for the induction of plasticity. It is now clear that the modulation of the AMPA receptor function and membrane trafficking is critical for many forms of synaptic plasticity and a large number of proteins have been identified that regulate this complex process. Here we review the progress over the last two and a half decades and discuss the future challenges in the field. Copyright © 2013 Elsevier Inc. All rights reserved.

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Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series.

Meizan Lai, Maartje GM Huijbers, Eric Lancaster … (2010)

Voltage-gated potassium channels are thought to be the target of antibodies associated with limbic encephalitis. However, antibody testing using cells expressing voltage-gated potassium channels is negative; hence, we aimed to identify the real autoantigen associated with limbic encephalitis. We analysed sera and CSF of 57 patients with limbic encephalitis and antibodies attributed to voltage-gated potassium channels and 148 control individuals who had other disorders with or without antibodies against voltage-gated potassium channels. Immunohistochemistry, immunoprecipitation, and mass spectrometry were used to characterise the antigen. An assay with HEK293 cells transfected with leucine-rich, glioma-inactivated 1 (LGI1) and disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) or ADAM23 was used as a serological test. The identity of the autoantigen was confirmed by immunoabsorption studies and immunostaining of Lgi1-null mice. Immunoprecipitation and mass spectrometry analyses showed that antibodies from patients with limbic encephalitis previously attributed to voltage-gated potassium channels recognise LGI1, a neuronal secreted protein that interacts with presynaptic ADAM23 and postsynaptic ADAM22. Immunostaining of HEK293 cells transfected with LGI1 showed that sera or CSF from patients, but not those from control individuals, recognised LGI1. Co-transfection of LGI1 with its receptors, ADAM22 or ADAM23, changed the pattern of reactivity and improved detection. LGI1 was confirmed as the autoantigen by specific abrogation of reactivity of sera and CSF from patients after immunoabsorption with LGI1-expressing cells and by comparative immunostaining of wild-type and Lgi1-null mice, which showed selective lack of reactivity in brains of Lgi1-null mice. One patient with limbic encephalitis and antibodies against LGI1 also had antibodies against CASPR2, an autoantigen we identified in some patients with encephalitis and seizures, Morvan's syndrome, and neuromyotonia. LGI1 is the autoantigen associated with limbic encephalitis previously attributed to voltage-gated potassium channels. The term limbic encephalitis associated with antibodies against voltage-gated potassium channels should be changed to limbic encephalitis associated with LGI1 antibodies, and this disorder should be classed as an autoimmune synaptic encephalopathy. National Institutes of Health, National Cancer Institute, and Euroimmun. Copyright 2010 Elsevier Ltd. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc Natl Acad Sci U S A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 19 January 2021

Publication date (Electronic): 04 January 2021

Publication date PMC-release: 04 January 2021

Volume: 118

Issue: 3

Electronic Location Identifier: e2022580118

Affiliations

[1] ^aDivision of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences , National Institutes of Natural Sciences, Aichi 444-8787, Japan;

[2] ^bDepartment of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies) , Aichi 444-8585, Japan;

[3] ^cDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco , CA 94158;

[4] ^dDepartment of Physiology, University of California, San Francisco , CA 94158;

[5] ^eDivision of System Neurophysiology, Department of System Neuroscience, National Institute for Physiological Sciences , National Institutes of Natural Sciences, Aichi 444-8585, Japan;

[6] ^fDepartment of Pediatrics, Graduate School of Medicine, The University of Tokyo , Tokyo 113-8655, Japan;

[7] ^gLaboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Kanagawa 230-0045, Japan;

[8] ^hCenter for Genetic Analysis of Behavior, National Institute for Physiological Sciences , National Institutes of Natural Sciences, Okazaki 444-8787, Japan;

[9] ⁱGerman Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany;

[10] ^jNeuroscience Research Center, Cluster NeuroCure, Charité-Universitätsmedizin Berlin , 10117 Berlin, Germany;

[11] ^kDepartment of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin , 10117 Berlin, Germany;

[12] ^lDepartment of Chemistry, Graduate School of Science, Kyoto University , 606-8502 Kyoto, Japan

Author notes

²To whom correspondence may be addressed. Email: nicoll@ 123456cmp.ucsf.edu or mfukata@ 123456nips.ac.jp .

Contributed by Roger A. Nicoll, December 1, 2020 (sent for review October 29, 2020; reviewed by David S. Bredt and Eunjoon Kim)

Author contributions: Y.F., A.N., S.F., R.A.N., and M.F. designed research; Y.F., R.A.N., and M.F. supervised the project; Y.F., X.C., S.C., Y.H., A.Y., H.I., M.S., H.S., T.G., M.H., S.F., R.A.N., and M.F. performed research; H.-C.K. and H.P. contributed new reagents/analytic tools; Y.F., X.C., S.C., Y.H., A.Y., H.S., A.N., S.F., R.A.N., and M.F. analyzed data; and Y.F., S.C., A.N., S.F., R.A.N., and M.F. wrote the paper.

Reviewers: D.S.B., Johnson and Johnson; and E.K., Korea Advanced Institute of Science and Technology.

¹Y.F. and X.C. contributed equally to this work.

Author information

Yuko Fukata https://orcid.org/0000-0001-7724-8643

Makoto Sanbo https://orcid.org/0000-0001-8806-1745

Hiromi Sano https://orcid.org/0000-0001-7347-8150

Teppei Goto https://orcid.org/0000-0002-0081-3357

Masumi Hirabayashi https://orcid.org/0000-0002-1059-5883

Hans-Christian Kornau https://orcid.org/0000-0003-4187-7549

Harald Prüss https://orcid.org/0000-0002-8283-7976

Atsushi Nambu https://orcid.org/0000-0003-2153-5445

Shuya Fukai https://orcid.org/0000-0002-1241-1443

Masaki Fukata https://orcid.org/0000-0001-5200-9806

Article

Publisher ID: 202022580

DOI: 10.1073/pnas.2022580118

PMC ID: 7826393

PubMed ID: 33397806

SO-VID: ade28ac8-1e6c-4c20-822d-51d593b5b536

License:

This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

History

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Pages: 12