title: Downregulation of GNA13-ERK network in prefrontal cortex of schizophrenia brain identified by combined focused and targeted quantitative proteomics.
abstract: 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.
  
  
  
  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.
authors.affiliation: Department of Pharmaceutical Microbiology, Faculty of Life Science, Kumamoto University 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; AMED-CREST, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda, Tokyo 100-0004, Japan.
authors.forename: Mio
authors.initials: M
authors.lastname: Hirayama-Kurogi
authors.affiliation: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University Sendai, Miyagi 980-8578, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Takizawa
authors.affiliation: Department of Neuropsychiatry, Fukushima Medical University School of Medicine, 960-1295 Fukushima, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Kunii
authors.affiliation: Department of Neuropsychiatry, Fukushima Medical University School of Medicine, 960-1295 Fukushima, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Matsumoto
authors.affiliation: Department of Neuropsychiatry, Fukushima Medical University School of Medicine, 960-1295 Fukushima, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Wada
authors.affiliation: Department of Neuropsychiatry, Fukushima Medical University School of Medicine, 960-1295 Fukushima, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Hino
authors.affiliation: Choju Medical Institute, Fukushimura Hospital, Noyori-cho, Toyohashi, Aichi 441-8124, Japan; Department of Community-based Medical Education, Nagoya City University Graduate School of Medical Science, Nagoya 467-8601, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Akatsu
authors.affiliation: Choju Medical Institute, Fukushimura Hospital, Noyori-cho, Toyohashi, Aichi 441-8124, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hashizume
authors.affiliation: Choju Medical Institute, Fukushimura Hospital, Noyori-cho, Toyohashi, Aichi 441-8124, Japan.
authors.forename: Sakon
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Pharmaceutical Microbiology, Faculty of Life Science, Kumamoto University 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; AMED-CREST, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda, Tokyo 100-0004, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Ito
authors.affiliation: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University Sendai, Miyagi 980-8578, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tachikawa
authors.affiliation: Department of Neuropsychiatry, Fukushima Medical University School of Medicine, 960-1295 Fukushima, Japan; Department of Psychiatry, Aizu Medical Center, Fukushima Medical University, 969-349 Fukushima, Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Niwa
authors.affiliation: Department of Neuropsychiatry, Fukushima Medical University School of Medicine, 960-1295 Fukushima, Japan.
authors.forename: Hirooki
authors.initials: H
authors.lastname: Yabe
authors.affiliation: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University Sendai, Miyagi 980-8578, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
authors.affiliation: AMED-CREST, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda, Tokyo 100-0004, Japan; Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan; Department of Systems Molecular Anatomy, Preeminent Medical Photonics Education & Research Center, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan; Riken Center for Molecular Imaging Science, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan; Department of Anatomy, The University of Hong Kong, 6/F, William MW Mong Block 21 Sassoon Road, Pokfulam, Hong Kong, China; Division of Neural Systematics, National Institute for Physiological Sciences, 38 Nishigonaka Myodaiji, Okazaki, Aichi, 444-8585, Japan; International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Setou
authors.affiliation: Department of Pharmaceutical Microbiology, Faculty of Life Science, Kumamoto University 5-1, Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; AMED-CREST, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda, Tokyo 100-0004, Japan. Electronic address: sohtsuki@kumamoto-u.ac.jp.
authors.forename: Sumio
authors.initials: S
authors.lastname: Ohtsuki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D015536:Down-Regulation; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D040901:Proteomics; D012559:Schizophrenia / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C109916:CYFIP1 protein, human; C491300:EIF4G2 protein, human; D039603:Eukaryotic Initiation Factor-4G; D048052:Mitogen-Activated Protein Kinase 3; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: GNA13; Molecular network; Prefrontal cortex; Quantitative proteomics; Schizophrenia; Targeted proteomics