Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms / Takafumi YUMOTO in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 68 p. 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 [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

Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines / Ryohei TAKADA in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 10p. Titre : Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines Type de document : Texte imprimé et/ou numérique Auteurs : Ryohei TAKADA, Auteur ; Michihiro TORITSUKA, Auteur ; Takahira YAMAUCHI, Auteur ; Rio ISHIDA, Auteur ; Yoshinori KAYASHIMA, Auteur ; Yuki NISHI, Auteur ; Mitsuru ISHIKAWA, Auteur ; Kazuhiko YAMAMURO, Auteur ; Minobu IKEHARA, Auteur ; Takashi KOMORI, Auteur ; Yuki NORIYAMA, Auteur ; Kohei KAMIKAWA, Auteur ; Yasuhiko SAITO, Auteur ; Hideyuki OKANO, Auteur ; Manabu MAKINODAN, Auteur Article en page(s) : 10p. Langues : Anglais (eng) Mots-clés : Female  Male  Humans  Cytokines  Granulocyte-Macrophage Colony-Stimulating Factor/metabolism/pharmacology  Macrophage Colony-Stimulating Factor/metabolism/pharmacology  Tumor Necrosis Factor-alpha/metabolism/pharmacology  Leukocytes, Mononuclear/metabolism  Interleukin-1alpha/metabolism/pharmacology  Autism Spectrum Disorder/metabolism  Cells, Cultured  Sexism  Macrophages/metabolism  Granulocytes/metabolism  Dendrites/metabolism  Autism spectrum disorder  Dendrite  Human iPS cell  Interleukin-1?  Macrophage  Tumor necrosis factor-? Index. décimale : PER Périodiques Résumé : BACKGROUND: A growing body of evidence suggests that immune dysfunction and inflammation in the peripheral tissues as well as the central nervous system are associated with the neurodevelopmental deficits observed in autism spectrum disorder (ASD). Elevated expression of pro-inflammatory cytokines in the plasma, serum, and peripheral blood mononuclear cells of ASD has been reported. These cytokine expression levels are associated with the severity of behavioral impairments and symptoms in ASD. In a prior study, our group reported that tumor necrosis factor-? (TNF-?) expression in granulocyte-macrophage colony-stimulating factor-induced macrophages (GM-CSF M?) and the TNF-? expression ratio in GM-CSF M?/M-CSF M? (macrophage colony-stimulating factor-induced macrophages) was markedly higher in individuals with ASD than in typically developed (TD) individuals. However, the mechanisms of how the macrophages and the highly expressed cytokines affect neurons remain to be addressed. METHODS: To elucidate the effect of macrophages on human neurons, we used a co-culture system of control human-induced pluripotent stem cell-derived neurons and differentiated macrophages obtained from the peripheral blood mononuclear cells of five TD individuals and five individuals with ASD. All participants were male and ethnically Japanese. RESULTS: Our results of co-culture experiments showed that GM-CSF M? affect the dendritic outgrowth of neurons through the secretion of pro-inflammatory cytokines, interleukin-1? and TNF-?. Macrophages derived from individuals with ASD exerted more severe effects than those derived from TD individuals. LIMITATIONS: The main limitations of our study were the small sample size with a gender bias toward males, the use of artificially polarized macrophages, and the inability to directly observe the interaction between neurons and macrophages from the same individuals. CONCLUSIONS: Our co-culture system revealed the non-cell autonomous adverse effects of GM-CSF M? in individuals with ASD on neurons, mediated by interleukin-1? and TNF-?. These results may support the immune dysfunction hypothesis of ASD, providing new insights into its pathology. En ligne : https://dx.doi.org/10.1186/s13229-024-00589-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Granulocyte macrophage colony-stimulating factor-induced macrophages of individuals with autism spectrum disorder adversely affect neuronal dendrites through the secretion of pro-inflammatory cytokines [Texte imprimé et/ou numérique] / Ryohei TAKADA, Auteur ; Michihiro TORITSUKA, Auteur ; Takahira YAMAUCHI, Auteur ; Rio ISHIDA, Auteur ; Yoshinori KAYASHIMA, Auteur ; Yuki NISHI, Auteur ; Mitsuru ISHIKAWA, Auteur ; Kazuhiko YAMAMURO, Auteur ; Minobu IKEHARA, Auteur ; Takashi KOMORI, Auteur ; Yuki NORIYAMA, Auteur ; Kohei KAMIKAWA, Auteur ; Yasuhiko SAITO, Auteur ; Hideyuki OKANO, Auteur ; Manabu MAKINODAN, Auteur . - 10p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 10p. Mots-clés : Female  Male  Humans  Cytokines  Granulocyte-Macrophage Colony-Stimulating Factor/metabolism/pharmacology  Macrophage Colony-Stimulating Factor/metabolism/pharmacology  Tumor Necrosis Factor-alpha/metabolism/pharmacology  Leukocytes, Mononuclear/metabolism  Interleukin-1alpha/metabolism/pharmacology  Autism Spectrum Disorder/metabolism  Cells, Cultured  Sexism  Macrophages/metabolism  Granulocytes/metabolism  Dendrites/metabolism  Autism spectrum disorder  Dendrite  Human iPS cell  Interleukin-1?  Macrophage  Tumor necrosis factor-? Index. décimale : PER Périodiques Résumé : BACKGROUND: A growing body of evidence suggests that immune dysfunction and inflammation in the peripheral tissues as well as the central nervous system are associated with the neurodevelopmental deficits observed in autism spectrum disorder (ASD). Elevated expression of pro-inflammatory cytokines in the plasma, serum, and peripheral blood mononuclear cells of ASD has been reported. These cytokine expression levels are associated with the severity of behavioral impairments and symptoms in ASD. In a prior study, our group reported that tumor necrosis factor-? (TNF-?) expression in granulocyte-macrophage colony-stimulating factor-induced macrophages (GM-CSF M?) and the TNF-? expression ratio in GM-CSF M?/M-CSF M? (macrophage colony-stimulating factor-induced macrophages) was markedly higher in individuals with ASD than in typically developed (TD) individuals. However, the mechanisms of how the macrophages and the highly expressed cytokines affect neurons remain to be addressed. METHODS: To elucidate the effect of macrophages on human neurons, we used a co-culture system of control human-induced pluripotent stem cell-derived neurons and differentiated macrophages obtained from the peripheral blood mononuclear cells of five TD individuals and five individuals with ASD. All participants were male and ethnically Japanese. RESULTS: Our results of co-culture experiments showed that GM-CSF M? affect the dendritic outgrowth of neurons through the secretion of pro-inflammatory cytokines, interleukin-1? and TNF-?. Macrophages derived from individuals with ASD exerted more severe effects than those derived from TD individuals. LIMITATIONS: The main limitations of our study were the small sample size with a gender bias toward males, the use of artificially polarized macrophages, and the inability to directly observe the interaction between neurons and macrophages from the same individuals. CONCLUSIONS: Our co-culture system revealed the non-cell autonomous adverse effects of GM-CSF M? in individuals with ASD on neurons, mediated by interleukin-1? and TNF-?. These results may support the immune dysfunction hypothesis of ASD, providing new insights into its pathology. En ligne : https://dx.doi.org/10.1186/s13229-024-00589-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

Structure and Function of Myelin Protein Genes / Katsuhiko MIKOSHIBA in Annual Review of Neuroscience, 14 (1991)

Public ISBD [article]  inAnnual Review of Neuroscience > 14 (1991) . - p.201-217 Titre : Structure and Function of Myelin Protein Genes Type de document : Texte imprimé et/ou numérique Auteurs : Katsuhiko MIKOSHIBA, Auteur ; Hideyuki OKANO, Auteur ; Taka-aki TAMURA, Auteur ; Kazuhiro IKENAKA, Auteur Année de publication : 1991 Article en page(s) : p.201-217 Langues : Anglais (eng) Mots-clés : Myelin basic protein - Myelin proteolipid protein - myeli-associated glycoprotein - Mutant mice - Gene expression Index. décimale : PER Périodiques Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=368 [article] Structure and Function of Myelin Protein Genes [Texte imprimé et/ou numérique] / Katsuhiko MIKOSHIBA, Auteur ; Hideyuki OKANO, Auteur ; Taka-aki TAMURA, Auteur ; Kazuhiro IKENAKA, Auteur . - 1991 . - p.201-217. Langues : Anglais (eng) in Annual Review of Neuroscience > 14 (1991) . - p.201-217 Mots-clés : Myelin basic protein - Myelin proteolipid protein - myeli-associated glycoprotein - Mutant mice - Gene expression Index. décimale : PER Périodiques Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=368

---

1 (1 - 3 / 3)