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

Autor: 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.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Jul 24; Vol. 14 (1), pp. 17097. Date of Electronic Publication: 2024 Jul 24.
DOI: 10.1038/s41598-024-68062-x
Abstrakt: 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).)
Databáze: MEDLINE
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