Soluble form of Lingo2, an autism spectrum disorder-associated molecule, functions as an excitatory synapse organizer in neurons.

Autor: Yoshida F; Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan., Nagatomo R; Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan., Utsunomiya S; Neuroscience 2, Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd, Osaka, Japan., Kimura M; Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan., Shun S; Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan., Kono R; Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan., Kato Y; Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan., Nao Y; Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan., Maeda K; Neuroscience 2, Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd, Osaka, Japan., Koyama R; Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.; Institute for AI and Beyond, The University of Tokyo, Tokyo, Japan.; 5Department of Translational Neurobiology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan., Ikegaya Y; Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.; Institute for AI and Beyond, The University of Tokyo, Tokyo, Japan.; Center for Information and Neural Networks, National Institute of Information and Communications Technology, Osaka, Japan., Lichtenthaler SF; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Takatori S; Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan., Takemoto H; Neuroscience 2, Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd, Osaka, Japan.; Business-Academia Collaborative Laboratory (Shionogi), Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan., Ogawa K; Neuroscience 2, Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd, Osaka, Japan., Ito G; Department of Biomolecular Chemistry, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan.; Social Cooperation Program of Brain and Neurological Disorders, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan., Tomita T; Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. taisuke@mol.f.u-tokyo.ac.jp.; Social Cooperation Program of Brain and Neurological Disorders, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan. taisuke@mol.f.u-tokyo.ac.jp.
Jazyk: angličtina
Zdroj: Translational psychiatry [Transl Psychiatry] 2024 Oct 23; Vol. 14 (1), pp. 448. Date of Electronic Publication: 2024 Oct 23.
DOI: 10.1038/s41398-024-03167-5
Abstrakt: Autism Spectrum Disorder (ASD) is a developmental disorder characterized by impaired social communication and repetitive behaviors. In recent years, a pharmacological mouse model of ASD involving maternal administration of valproic acid (VPA) has become widely used. Newborn pups in this model show an abnormal balance between excitatory and inhibitory (E/I) signaling in neurons and exhibit ASD-like behavior. However, the molecular basis of this model and its implications for the pathogenesis of ASD in humans remain unknown. Using quantitative secretome analysis, we found that the level of leucine-rich repeat and immunoglobulin domain-containing protein 2 (Lingo2) was upregulated in the conditioned medium of VPA model neurons. This upregulation was associated with excitatory synaptic organizer activity. The secreted form of the extracellular domain of Lingo2 (sLingo2) is produced by the transmembrane metalloprotease ADAM10 through proteolytic processing. sLingo2 was found to induce the formation of excitatory synapses in both mouse and human neurons, and treatment with sLingo2 resulted in an increased frequency of miniature excitatory postsynaptic currents in human neurons. These findings suggest that sLingo2 is an excitatory synapse organizer involved in ASD, and further understanding of the mechanisms by which sLingo2 induces excitatory synaptogenesis is expected to advance our understanding of the pathogenesis of ASD.
(© 2024. The Author(s).)
Databáze: MEDLINE
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