TY - JOUR
T1 - Downregulation of GNA13-ERK network in prefrontal cortex of schizophrenia brain identified by combined focused and targeted quantitative proteomics
AU - Hirayama-Kurogi, Mio
AU - Takizawa, Yohei
AU - Kunii, Yasuto
AU - Matsumoto, Junya
AU - Wada, Akira
AU - Hino, Mizuki
AU - Akatsu, Hiroyasu
AU - Hashizume, Yoshio
AU - Yamamoto, Sakon
AU - Kondo, Takeshi
AU - Ito, Shingo
AU - Tachikawa, Masanori
AU - Niwa, Shin Ichi
AU - Yabe, Hirooki
AU - Terasaki, Tetsuya
AU - Setou, Mitsutoshi
AU - Ohtsuki, Sumio
N1 - Funding Information:
This study was supported by grants from the Ministry of Health, Houga Research, Exploratory Research for Young Scientists (B) from the Ministry of Education, Science, Sports, and Culture of Japan (No. 26860057); and from the Japanese Society for the Promotion of Science (No. 26640092), AMED-CREST from Japan Agency for Medical Research and Development (No. 10801082), and the Funding Program for Next Generation World-Leading Researchers by the Cabinet Office, Government of Japan (No. LS005) and from Stem cell-based tissue regeneration research and education unit”, Kumamoto University.
Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/3/31
Y1 - 2017/3/31
N2 - Schizophrenia is a disabling mental illness associated with dysfunction of the prefrontal cortex, which affects cognition and emotion. The purpose of the present study was to identify altered molecular networks in the prefrontal cortex of schizophrenia patients by comparing protein expression levels in autopsied brains of patients and controls, using a combination of targeted and focused quantitative proteomics. We selected 125 molecules possibly related to schizophrenia for quantification by knowledge-based targeted proteomics. Among the quantified molecules, GRIK4 and MAO-B were significantly decreased in plasma membrane and cytosolic fractions, respectively, of prefrontal cortex. Focused quantitative proteomics identified 15 increased and 39 decreased proteins. Network analysis identified “GNA13-ERK1-eIF4G2 signaling” as a downregulated network, and proteins involved in this network were significantly decreased. Furthermore, searching downstream of eIF4G2 revealed that eIF4A1/2 and CYFIP1 were decreased, suggesting that downregulation of the network suppresses expression of CYFIP1, which regulates actin remodeling and is involved in axon outgrowth and spine formation. Downregulation of this signaling seems likely to impair axon formation and synapse plasticity of neuronal cells, and could be associated with development of cognitive impairment in the pathology of schizophrenia. Biological significance The present study compared the proteome of the prefrontal cortex between schizophrenia patients and healthy controls by means of targeted proteomics and global quantitative proteomics. Targeted proteomics revealed that GRIK4 and MAOB were significantly decreased among 125 putatively schizophrenia-related proteins in prefrontal cortex of schizophrenia patients. Global quantitative proteomics identified 54 differentially expressed proteins in schizophrenia brains. The protein profile indicates attenuation of “GNA13-ERK signaling” in schizophrenia brain. In particular, EIF4G2 and CYFIP1, which are located downstream of the GNA13-ERK network, were decreased, suggesting that the attenuation of this signal network may cause impairment of axon formation and synapse plasticity in the brain of schizophrenia patients. Our results provide a novel insight into schizophrenia pathology, and could be helpful for drug development.
AB - Schizophrenia is a disabling mental illness associated with dysfunction of the prefrontal cortex, which affects cognition and emotion. The purpose of the present study was to identify altered molecular networks in the prefrontal cortex of schizophrenia patients by comparing protein expression levels in autopsied brains of patients and controls, using a combination of targeted and focused quantitative proteomics. We selected 125 molecules possibly related to schizophrenia for quantification by knowledge-based targeted proteomics. Among the quantified molecules, GRIK4 and MAO-B were significantly decreased in plasma membrane and cytosolic fractions, respectively, of prefrontal cortex. Focused quantitative proteomics identified 15 increased and 39 decreased proteins. Network analysis identified “GNA13-ERK1-eIF4G2 signaling” as a downregulated network, and proteins involved in this network were significantly decreased. Furthermore, searching downstream of eIF4G2 revealed that eIF4A1/2 and CYFIP1 were decreased, suggesting that downregulation of the network suppresses expression of CYFIP1, which regulates actin remodeling and is involved in axon outgrowth and spine formation. Downregulation of this signaling seems likely to impair axon formation and synapse plasticity of neuronal cells, and could be associated with development of cognitive impairment in the pathology of schizophrenia. Biological significance The present study compared the proteome of the prefrontal cortex between schizophrenia patients and healthy controls by means of targeted proteomics and global quantitative proteomics. Targeted proteomics revealed that GRIK4 and MAOB were significantly decreased among 125 putatively schizophrenia-related proteins in prefrontal cortex of schizophrenia patients. Global quantitative proteomics identified 54 differentially expressed proteins in schizophrenia brains. The protein profile indicates attenuation of “GNA13-ERK signaling” in schizophrenia brain. In particular, EIF4G2 and CYFIP1, which are located downstream of the GNA13-ERK network, were decreased, suggesting that the attenuation of this signal network may cause impairment of axon formation and synapse plasticity in the brain of schizophrenia patients. Our results provide a novel insight into schizophrenia pathology, and could be helpful for drug development.
KW - GNA13
KW - Molecular network
KW - Prefrontal cortex
KW - Quantitative proteomics
KW - Schizophrenia
KW - Targeted proteomics
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UR - http://www.scopus.com/inward/citedby.url?scp=85013643308&partnerID=8YFLogxK
U2 - 10.1016/j.jprot.2017.02.009
DO - 10.1016/j.jprot.2017.02.009
M3 - Article
C2 - 28214564
AN - SCOPUS:85013643308
VL - 158
SP - 31
EP - 42
JO - Journal of Biochemical and Biophysical Methods
JF - Journal of Biochemical and Biophysical Methods
SN - 1874-3919
ER -