TY - JOUR
T1 - GNAO1 organizes the cytoskeletal remodeling and firing of developing neurons
AU - Akamine, Satoshi
AU - Okuzono, Sayaka
AU - Yamamoto, Hiroyuki
AU - Setoyama, Daiki
AU - Sagata, Noriaki
AU - Ohgidani, Masahiro
AU - Kato, Takahiro A.
AU - Ishitani, Tohru
AU - Kato, Hiroki
AU - Masuda, Keiji
AU - Matsushita, Yuki
AU - Ono, Hiroaki
AU - Ishizaki, Yoshito
AU - Sanefuji, Masafumi
AU - Saitsu, Hirotomo
AU - Matsumoto, Naomichi
AU - Kang, Dongchon
AU - Kanba, Shigenobu
AU - Nakabeppu, Yusaku
AU - Sakai, Yasunari
AU - Ohga, Shouichi
N1 - Funding Information:
We thank the patients and their parents for kindly cooperating with this study; Drs. Toshiro Hara (Fukuoka Children's Hospital) and Kazuaki Nonaka (Professor Emeritus, Kyushu University) for cordial supports of this research; Dr Huda Y Zoghbi (Neurological Research Institute, Texas) for the critical review of this manuscript; and Dr Brian Quinn for proofreading this manuscript. This study was supported by JSPS KAKENHI grant numbers 19K08281, (Y. Sakai), 18H04042 (T.A. Kato), 18K07821(Y. Ishizaki) and 17H01539 (N. Matsumoto); AMED under the grant numbers JP19ek0109411/JP20ek0109411, JP20wm0325002, JP19ek0410039 (Y. Sakai), JP20ek0109486, JP20ek0109348, JP20kk0205012 (N. Matsumoto); a Health and Labour Sciences Research Grant (N. Matsumoto), that on Evidence‐based Early Diagnosis and Treatment Strategies for Neuroimmunological Diseases from the Ministry of Health, Labour and Welfare of Japan (Y. Sakai); Life Science Foundation of Japan (Y. Sakai); Takeda Science Foundation (Y. Sakai, N. Matsumoto); The Mother and Child Health Foundation (Y. Sakai), The Japan Epilepsy Research Foundation (Y. Sakai), and Kawano Masanori Memorial Public InterestIncorporated Foundation for Promotion of Pediatrics (Y. Sakai).
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
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U2 - 10.1096/fj.202001113R
DO - 10.1096/fj.202001113R
M3 - Article
AN - SCOPUS:85093916124
VL - 34
SP - 16601
EP - 16621
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 12
ER -