دورية أكاديمية
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Gnao1 is a molecular switch that regulates the Rho signaling pathway in differentiating neurons.

التفاصيل البيبلوغرافية
العنوان: Gnao1 is a molecular switch that regulates the Rho signaling pathway in differentiating neurons.
المؤلفون: Taira R; Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Highashi-ku, Fukuoka, 812-8582, Japan.; Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan., Akamine S; Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Highashi-ku, Fukuoka, 812-8582, Japan., Okuzono S; Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Highashi-ku, Fukuoka, 812-8582, Japan., Fujii F; Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Highashi-ku, Fukuoka, 812-8582, Japan., Hatai E; Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Highashi-ku, Fukuoka, 812-8582, Japan., Yonemoto K; Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Highashi-ku, Fukuoka, 812-8582, Japan., Takemoto R; Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Highashi-ku, Fukuoka, 812-8582, Japan., Kato H; Department of Molecular Cell Biology and Oral Anatomy, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan., Masuda K; Section of Oral Medicine for Children, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Fukuoka, Japan., Kato TA; Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Kira R; Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan., Tsujimura K; Group of Brain Function and Development, Neuroscience Institute of the Graduate School of Science, Nagoya University, Aichi, Japan.; Research Unit for Developmental Disorders, Institute for Advanced Research, Nagoya University, Nagoya, Japan.; Shionogi Pharma Co., Ltd., Settsu, Osaka, Japan., Yamamura K; Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Highashi-ku, Fukuoka, 812-8582, Japan., Ozaki N; Pathophysiology of Mental Disorders, Nagoya University Graduate School of Medicine, Nagoya, Japan., Ohga S; Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Highashi-ku, Fukuoka, 812-8582, Japan., Sakai Y; Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Highashi-ku, Fukuoka, 812-8582, Japan. sakai.yasunari.530@m.kyushu-u.ac.jp.
المصدر: Scientific reports [Sci Rep] 2024 Jul 24; Vol. 14 (1), pp. 17097. Date of Electronic Publication: 2024 Jul 24.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Publishing Group, copyright 2011-
مواضيع طبية MeSH: GTP-Binding Protein alpha Subunits, Gi-Go*/metabolism , GTP-Binding Protein alpha Subunits, Gi-Go*/genetics , Neurons*/metabolism , Signal Transduction* , Induced Pluripotent Stem Cells*/metabolism , Induced Pluripotent Stem Cells*/cytology , rho GTP-Binding Proteins*/metabolism , rho GTP-Binding Proteins*/genetics , Cell Differentiation*, Humans ; Mice ; Animals ; rho-Associated Kinases/metabolism ; Organoids/metabolism ; Amides/pharmacology ; Pyridines
مستخلص: GNAO1 encodes G protein subunit alpha O1 (Gαo). Pathogenic variations in GNAO1 cause developmental delay, intractable seizures, and progressive involuntary movements from early infancy. Because the functional role of GNAO1 in the developing brain remains unclear, therapeutic strategies are still unestablished for patients presenting with GNAO1-associated encephalopathy. We herein report that siRNA-mediated depletion of Gnao1 perturbs the expression of transcripts associated with Rho GTPase signaling in Neuro2a cells. Consistently, siRNA treatment hampered neurite outgrowth and extension. Growth cone formation was markedly disrupted in monolayer neurons differentiated from iPSCs from a patient with a pathogenic variant of Gαo (p.G203R). This variant disabled neuro-spherical assembly, acquisition of the organized structure, and polarized signals of phospho-MLC2 in cortical organoids from the patient's iPSCs. We confirmed that the Rho kinase inhibitor Y27632 restored these morphological phenotypes. Thus, Gαo determines the self-organizing process of the developing brain by regulating the Rho-associated pathway. These data suggest that Rho GTPase pathway might be an alternative target of therapy for patients with GNAO1-associated encephalopathy.
(© 2024. The Author(s).)
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معلومات مُعتمدة: JP22K15913; JP21K07865; JP23K07334 Japan Society for the Promotion of Science; JP22K15913; JP21K07865; JP23K07334 Japan Society for the Promotion of Science; JP22K15913; JP21K07865; JP23K07334 Japan Society for the Promotion of Science; JP22K15913; JP21K07865; JP23K07334 Japan Society for the Promotion of Science; JP22K15913; JP21K07865; JP23K07334 Japan Society for the Promotion of Science; JP20ek0109411; JP23wm0325069 Japan Agency for Medical Research and Development; JP23FC0201; JP21FC1005 Ministry of Health, Labour and Welfare
فهرسة مساهمة: Keywords: GNAO1; Developmental and epileptic encephalopathy; Differentiation; Molecular pathway; Organoids; Rho-associated kinase
المشرفين على المادة: EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
0 (GNAO1 protein, human)
EC 3.6.5.2 (rho GTP-Binding Proteins)
EC 2.7.11.1 (rho-Associated Kinases)
138381-45-0 (Y 27632)
0 (Amides)
0 (Pyridines)
تواريخ الأحداث: Date Created: 20240724 Date Completed: 20240725 Latest Revision: 20240728
رمز التحديث: 20240728
مُعرف محوري في PubMed: PMC11269603
DOI: 10.1038/s41598-024-68062-x
PMID: 39048611
قاعدة البيانات: MEDLINE
الوصف
تدمد:2045-2322
DOI:10.1038/s41598-024-68062-x