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Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms / Takafumi YUMOTO in Molecular Autism, 11 (2020)
[article]
Titre : Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms Type de document : Texte imprimé et/ou numérique Auteurs : Takafumi YUMOTO, Auteur ; Misaki KIMURA, Auteur ; Ryota NAGATOMO, Auteur ; Tsukika SATO, Auteur ; Shun UTSUNOMIYA, Auteur ; Natsue AOKI, Auteur ; Motoji KITAURA, Auteur ; Koji TAKAHASHI, Auteur ; Hiroshi TAKEMOTO, Auteur ; Hirotaka WATANABE, Auteur ; Hideyuki OKANO, Auteur ; Fumiaki YOSHIDA, Auteur ; Yosuke NAO, Auteur ; Taisuke TOMITA, Auteur Article en page(s) : 68 p. Langues : Anglais (eng) Mots-clés : Neuroligin 4X Proteolysis Synaptogenesis Trafficking Index. décimale : PER Périodiques Résumé : BACKGROUND: Several genetic alterations, including point mutations and copy number variations in NLGN genes, have been associated with psychiatric disorders, such as autism spectrum disorder (ASD) and X-linked mental retardation (XLMR). NLGN genes encode neuroligin (NL) proteins, which are adhesion molecules that are important for proper synaptic formation and maturation. Previously, we and others found that the expression level of murine NL1 is regulated by proteolytic processing in a synaptic activity-dependent manner. METHODS: In this study, we analyzed the effects of missense variants associated with ASD and XLMR on the metabolism and function of NL4X, a protein which is encoded by the NLGN4X gene and is expressed only in humans, using cultured cells, primary neurons from rodents, and human induced pluripotent stem cell-derived neurons. RESULTS: NL4X was found to undergo proteolytic processing in human neuronal cells. Almost all NL4X variants caused a substantial decrease in the levels of mature NL4X and its synaptogenic activity in a heterologous culture system. Intriguingly, the L593F variant of NL4X accelerated the proteolysis of mature NL4X proteins located on the cell surface. In contrast, other variants decreased the cell-surface trafficking of NL4X. Notably, protease inhibitors as well as chemical chaperones rescued the expression of mature NL4X. LIMITATIONS: Our study did not reveal whether these dysfunctional phenotypes occurred in individuals carrying NLGN4X variant. Moreover, though these pathological mechanisms could be exploited as potential drug targets for ASD, it remains unclear whether these compounds would have beneficial effects on ASD model animals and patients. CONCLUSIONS: These data suggest that reduced amounts of the functional NL4X protein on the cell surface is a common mechanism by which point mutants of the NL4X protein cause psychiatric disorders, although different molecular mechanisms are thought to be involved. Furthermore, these results highlight that the precision medicine approach based on genetic and cell biological analyses is important for the development of therapeutics for psychiatric disorders. En ligne : http://dx.doi.org/10.1186/s13229-020-00373-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433
in Molecular Autism > 11 (2020) . - 68 p.[article] Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms [Texte imprimé et/ou numérique] / Takafumi YUMOTO, Auteur ; Misaki KIMURA, Auteur ; Ryota NAGATOMO, Auteur ; Tsukika SATO, Auteur ; Shun UTSUNOMIYA, Auteur ; Natsue AOKI, Auteur ; Motoji KITAURA, Auteur ; Koji TAKAHASHI, Auteur ; Hiroshi TAKEMOTO, Auteur ; Hirotaka WATANABE, Auteur ; Hideyuki OKANO, Auteur ; Fumiaki YOSHIDA, Auteur ; Yosuke NAO, Auteur ; Taisuke TOMITA, Auteur . - 68 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 68 p.
Mots-clés : Neuroligin 4X Proteolysis Synaptogenesis Trafficking Index. décimale : PER Périodiques Résumé : BACKGROUND: Several genetic alterations, including point mutations and copy number variations in NLGN genes, have been associated with psychiatric disorders, such as autism spectrum disorder (ASD) and X-linked mental retardation (XLMR). NLGN genes encode neuroligin (NL) proteins, which are adhesion molecules that are important for proper synaptic formation and maturation. Previously, we and others found that the expression level of murine NL1 is regulated by proteolytic processing in a synaptic activity-dependent manner. METHODS: In this study, we analyzed the effects of missense variants associated with ASD and XLMR on the metabolism and function of NL4X, a protein which is encoded by the NLGN4X gene and is expressed only in humans, using cultured cells, primary neurons from rodents, and human induced pluripotent stem cell-derived neurons. RESULTS: NL4X was found to undergo proteolytic processing in human neuronal cells. Almost all NL4X variants caused a substantial decrease in the levels of mature NL4X and its synaptogenic activity in a heterologous culture system. Intriguingly, the L593F variant of NL4X accelerated the proteolysis of mature NL4X proteins located on the cell surface. In contrast, other variants decreased the cell-surface trafficking of NL4X. Notably, protease inhibitors as well as chemical chaperones rescued the expression of mature NL4X. LIMITATIONS: Our study did not reveal whether these dysfunctional phenotypes occurred in individuals carrying NLGN4X variant. Moreover, though these pathological mechanisms could be exploited as potential drug targets for ASD, it remains unclear whether these compounds would have beneficial effects on ASD model animals and patients. CONCLUSIONS: These data suggest that reduced amounts of the functional NL4X protein on the cell surface is a common mechanism by which point mutants of the NL4X protein cause psychiatric disorders, although different molecular mechanisms are thought to be involved. Furthermore, these results highlight that the precision medicine approach based on genetic and cell biological analyses is important for the development of therapeutics for psychiatric disorders. En ligne : http://dx.doi.org/10.1186/s13229-020-00373-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 A Common Susceptibility Factor of Both Autism and Epilepsy: Functional Deficiency of GABAA Receptors / Jing-Qiong KANG in Journal of Autism and Developmental Disorders, 43-1 (January 2013)
[article]
Titre : A Common Susceptibility Factor of Both Autism and Epilepsy: Functional Deficiency of GABAA Receptors Type de document : Texte imprimé et/ou numérique Auteurs : Jing-Qiong KANG, Auteur ; Gregory BARNES, Auteur Article en page(s) : p.68-79 Langues : Anglais (eng) Mots-clés : Autism Epilepsy Co-morbidity GABAA receptor Brain development Synaptogenesis Index. décimale : PER Périodiques Résumé : Autism and epilepsy are common childhood neurological disorders with a great heterogeneity of clinical phenotypes as well as risk factors. There is a high co-morbidity of autism and epilepsy. The neuropathology of autism and epilepsy has similar histology implicating the processes of neurogenesis, neural migration, programmed cell death, and neurite outgrowth. Genetic advances have identified multiple molecules that participate in neural development, brain network connectivity, and synaptic function which are involved in the pathogenesis of autism and epilepsy. Mutations in GABAA receptor subunit have been frequently associated with epilepsy, autism, and other neuropsychiatric disorders. In this paper, we address the hypothesis that functional deficiency of GABAergic signaling is a potential common molecular mechanism underpinning the co-morbidity of autism and epilepsy. En ligne : http://dx.doi.org/10.1007/s10803-012-1543-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=187
in Journal of Autism and Developmental Disorders > 43-1 (January 2013) . - p.68-79[article] A Common Susceptibility Factor of Both Autism and Epilepsy: Functional Deficiency of GABAA Receptors [Texte imprimé et/ou numérique] / Jing-Qiong KANG, Auteur ; Gregory BARNES, Auteur . - p.68-79.
Langues : Anglais (eng)
in Journal of Autism and Developmental Disorders > 43-1 (January 2013) . - p.68-79
Mots-clés : Autism Epilepsy Co-morbidity GABAA receptor Brain development Synaptogenesis Index. décimale : PER Périodiques Résumé : Autism and epilepsy are common childhood neurological disorders with a great heterogeneity of clinical phenotypes as well as risk factors. There is a high co-morbidity of autism and epilepsy. The neuropathology of autism and epilepsy has similar histology implicating the processes of neurogenesis, neural migration, programmed cell death, and neurite outgrowth. Genetic advances have identified multiple molecules that participate in neural development, brain network connectivity, and synaptic function which are involved in the pathogenesis of autism and epilepsy. Mutations in GABAA receptor subunit have been frequently associated with epilepsy, autism, and other neuropsychiatric disorders. In this paper, we address the hypothesis that functional deficiency of GABAergic signaling is a potential common molecular mechanism underpinning the co-morbidity of autism and epilepsy. En ligne : http://dx.doi.org/10.1007/s10803-012-1543-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=187