GNAO1 organizes the cytoskeletal remodeling and firing of developing neurons.
Satoshi AkamineSayaka OkuzonoHiroyuki YamamotoDaiki SetoyamaNoriaki SagataMasahiro OhgidaniTakahiro A KatoTohru IshitaniHiroki KatoKeiji MasudaYuki MatsushitaHiroaki OnoYoshito IshizakiMasafumi SanefujiHirotomo SaitsuNaomichi MatsumotoDongchon KangShigenobu KanbaYusaku NakabeppuYasunari SakaiShouichi OhgaPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2020)
Developmental and epileptic encephalopathy (DEE) represents a group of neurodevelopmental disorders characterized by infantile-onset intractable seizures and unfavorable prognosis of psychomotor development. To date, hundreds of genes have been linked to the onset of DEE. GNAO1 is a DEE-associated gene encoding the alpha-O1 subunit of guanine nucleotide-binding protein (GαO ). Despite the increasing number of reported children with GNAO1 encephalopathy, the molecular mechanisms underlying their neurodevelopmental phenotypes remain elusive. We herein present that co-immunoprecipitation and mass spectrometry analyses identified another DEE-associated protein, SPTAN1, as an interacting partner of GαO . Silencing of endogenous Gnao1 attenuated the neurite outgrowth and calcium-dependent signaling. Inactivation of GNAO1 in human-induced pluripotent stem cells gave rise to anomalous brain organoids that only weakly expressed SPTAN1 and Ankyrin-G. Furthermore, GNAO1-deficient organoids failed to conduct synchronized firing to adjacent neurons. These data indicate that GαO and other DEE-associated proteins organize the cytoskeletal remodeling and functional polarity of neurons in the developing brain.
Keyphrases
- induced pluripotent stem cells
- mass spectrometry
- spinal cord
- binding protein
- resting state
- genome wide
- early onset
- endothelial cells
- functional connectivity
- dna methylation
- gene expression
- machine learning
- big data
- protein kinase
- brain injury
- congenital heart disease
- cerebral ischemia
- subarachnoid hemorrhage
- genome wide analysis
- men who have sex with men
- ms ms
- pluripotent stem cells