Gnao1 is a molecular switch that regulates the Rho signaling pathway in differentiating neurons.
Humans
GTP-Binding Protein alpha Subunits, Gi-Go
/ metabolism
Neurons
/ metabolism
Signal Transduction
Induced Pluripotent Stem Cells
/ metabolism
rho GTP-Binding Proteins
/ metabolism
Cell Differentiation
Mice
Animals
rho-Associated Kinases
/ metabolism
Organoids
/ metabolism
Amides
/ pharmacology
Pyridines
GNAO1
Developmental and epileptic encephalopathy
Differentiation
Molecular pathway
Organoids
Rho-associated kinase
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
24 Jul 2024
24 Jul 2024
Historique:
received:
29
03
2024
accepted:
19
07
2024
medline:
26
7
2024
pubmed:
26
7
2024
entrez:
24
7
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39048611
doi: 10.1038/s41598-024-68062-x
pii: 10.1038/s41598-024-68062-x
doi:
Substances chimiques
GTP-Binding Protein alpha Subunits, Gi-Go
EC 3.6.5.1
GNAO1 protein, human
0
rho GTP-Binding Proteins
EC 3.6.5.2
rho-Associated Kinases
EC 2.7.11.1
Y 27632
138381-45-0
Amides
0
Pyridines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
17097Subventions
Organisme : Japan Society for the Promotion of Science
ID : JP22K15913; JP21K07865; JP23K07334
Organisme : Japan Society for the Promotion of Science
ID : JP22K15913; JP21K07865; JP23K07334
Organisme : Japan Society for the Promotion of Science
ID : JP22K15913; JP21K07865; JP23K07334
Organisme : Japan Society for the Promotion of Science
ID : JP22K15913; JP21K07865; JP23K07334
Organisme : Japan Society for the Promotion of Science
ID : JP22K15913; JP21K07865; JP23K07334
Organisme : Japan Agency for Medical Research and Development
ID : JP20ek0109411; JP23wm0325069
Organisme : Ministry of Health, Labour and Welfare
ID : JP23FC0201; JP21FC1005
Informations de copyright
© 2024. The Author(s).
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