Elucidating the synaptic pathology of neurodevelopmental disorders-Comprehensive and quantitative analysis of signaling pathway abnormalities

• Project/Area Number: 16K15554
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Psychiatric science
• Research Institution: Niigata University
• Principal Investigator: Someya Toshiyuki 新潟大学, 医歯学系, 教授 (50187902)
• Research Collaborator: Igarashi Michihiro ; Egawa Jun
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 統合失調症 / 自閉症 / リン酸化プロテオミクス / GAP43 / NLGN3 / 神経発達障害 / シナプス画分 / 機能解析 / 児童思春期精神医学 / 神経生化学

Outline of Final Research Achievements

We selected GAP43 and NLGN3, which are risk genes for schizophrenia and autism, among genes whose phosphorylation sites are important for neurodevelopment identified by phosphoproteomics of growth cones, and performed functional analysis. The GAP43 D23G mutation identified in an autism patient was introduced into Hela cells and observed immunohistologically. The results revealed that D23G-transduced cells showed less nuclear expression of GAP43 than wild-type transfected cells. Furthermore, the distribution of the phosphorylation site (S745) of NLGN3 was subjected to immunoblotting using synaptosomes, and immunohistological observation using primary culture neurons. These findings suggest that phosphorylation may be functional at both the axonal tip and the synapse.

Academic Significance and Societal Importance of the Research Achievements

統合失調症や自閉症の妥当性の高いリスク遺伝子は全エクソーム解析などの網羅的な解析法によって同定された。本研究ではタンパクレベルの網羅的解析であるリン酸化プロテオミクスで同定された神経発達に重要と考えられるリン酸化部位のうち統合失調および自閉症のリスク遺伝子に存在するものを選定してそれらの機能についての知見を得ることができた。タンパクレベルの妥当性の高い知見を蓄積することにより、さらに高次レベルの知見を得るための確かな土台となる。このように各レベルで妥当性の高い土台を重ねていくことにより、それらの疾患の病態解明および治療法開発に結び付くと考えられる。。

Research Products

• [Journal Article] Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. (2018)
  • Author(s): Kushima I, (27名中略）, Hashimoto R,(80名中29番目) , et al.
  • Journal Title: Cell Rep Volume: 24(11) Issue: 11 Pages: 2838-2856
  • DOI: 10.1016/j.celrep.2018.08.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pathological alterations of chondroitin sulfate moiety in postmortem hippocampus of patients with schizophrenia (2018)
  • Author(s): Yukawa、Iwakura、Takei、Saito、Watanabe、Toyooka、Igarashi、Niizato、Oshima、Kunii、Yabe、Matsumoto、Wada、Hino、Iritanii、Niwa、Takeuchi、Takahashi、Kakita、Someya、Nawa
  • Journal Title: Psychiatry Research Volume: 270 Pages: 940-946
  • DOI: 10.1016/j.psychres.2018.10.062
  • Peer Reviewed / Open Access
• [Journal Article] Longer telomeres in elderly schizophrenia are associated with long-term hospitalization in the Japanese population. (2018)
  • Author(s): Zhang Y, Hishimoto A, Otsuka I, Watanabe Y, Numata S, Yamamori H, Boku S, Horai T, Someya T, Ohmori T, Hashimoto R, Sora I.
  • Journal Title: J Psychiatr Res Volume: 103 Pages: 161-166
  • DOI: 10.1016/j.jpsychires.2018.05.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of olanzapine on resting heart rate in Japanese patients with schizophrenia (2018)
  • Author(s): Tajiri M、Suzuki Y、Sugai T、Tsuneyama N、Someya T
  • Journal Title: PLOS ONE Volume: 13 Issue: 7 Pages: e0199922-e0199922
  • DOI: 10.1371/journal.pone.0199922
  • Peer Reviewed / Open Access
• [Journal Article] High-density lipoprotein-cholesterol and antipsychotic medication in overweight inpatients with schizophrenia: post-hoc analysis of a Japanese nationwide survey. (2018)
  • Author(s): Ono S, Sugai T, Suzuki Y, Yamazaki M, Shimoda K, Mori T, Ozeki Y, Matsuda H, Sugawara N, Yasui-Furukori N, Okamoto K, Sagae T, Someya T.
  • Journal Title: BMC Psychiatry Volume: 18 Issue: 1 Pages: 180-180
  • DOI: 10.1186/s12888-018-1764-1
  • Peer Reviewed / Open Access
• [Journal Article] Prevalence of underweight in patients with schizophrenia: A meta-analysis (2018)
  • Author(s): Sugawara N、Maruo K、Sugai T、Suzuki Y、Ozeki Y、Shimoda K、Someya T、Yasui-Furukori N
  • Journal Title: Schizophrenia Research Volume: 195 Pages: 67-73
  • DOI: 10.1016/j.schres.2017.10.017
  • Peer Reviewed
• [Journal Article] Heterogeneous Redistribution of Facial Subcategory Information Within and Outside the Face-Selective Domain in Primate Inferior Temporal Cortex (2018)
  • Author(s): Miyakawa Naohisa、Majima Kei、Sawahata Hirohito、Kawasaki Keisuke、Matsuo Takeshi、Kotake Naoki、Suzuki Takafumi、Kamitani Yukiyasu、Hasegawa Isao
  • Journal Title: Cerebral Cortex Volume: 28 Issue: 4 Pages: 1416-1431
  • DOI: 10.1093/cercor/bhx342
  • Peer Reviewed / Open Access
• [Journal Article] Locally induced neuronal synchrony precisely propagates to specific cortical areas without rhythm distortion. (2018)
  • Author(s): Toda H, Kawasaki K, Sato S, Horie M, Nakahara K, Bepari AK, Sawahata H, Suzuki T, Okado H, Takebayashi H, Hasegawa I.
  • Journal Title: Scientific Reports Volume: - Issue: 1 Pages: 7678-7678
  • DOI: 10.1038/s41598-018-26054-8
  • Peer Reviewed / Open Access
• [Journal Article] Rare loss of function mutations in N-methyl-d-aspartate glutamate receptors and their contributions to schizophrenia susceptibility (2018)
  • Author(s): Yu Yanjie、Lin Yingni、Takasaki Yuto、Wang Chenyao、Kimura Hiroki、Xing Jingrui、Ishizuka Kanako、Toyama Miho、Kushima Itaru、Mori Daisuke、Arioka Yuko、Uno Yota、Shiino Tomoko、Nakamura Yukako、Okada Takashi、Morikawa Mako、Ikeda Masashi、Iwata Nakao、Okahisa Yuko、Takaki Manabu、Sakamoto Shinji、et al.
  • Journal Title: Translational Psychiatry Volume: 8 Issue: 1 Pages: 12-20
  • DOI: 10.1038/s41398-017-0061-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rare PDCD11 variations are not associated with risk of schizophrenia in Japan (2017)
  • Author(s): Hoya Satoshi、Watanabe Yuichiro、Hishimoto Akitoyo、Nunokawa Ayako、Kaneko Naoshi、Muratake Tatsuyuki、Shinmyo Naofumi、Otsuka Ikuo、Okuda Shujiro、Inoue Emiko、Igeta Hirofumi、Shibuya Masako、Egawa Jun、Orime Naoki、Sora Ichiro、Someya Toshiyuki
  • Journal Title: Psychiatry and Clinical Neurosciences Volume: 71 Issue: 11 Pages: 780-788
  • DOI: 10.1111/pcn.12549
  • Peer Reviewed / Open Access
• [Journal Article] Rare FBOX18 variations and risk of schizophrenia: whole-exome sequencing in two parent-affected offspring trios followed by resequencing and case-control studies. (2017)
  • Author(s): Hoya S, Watabe Y, Hishimoto A, Nunokawa A, Inoue E, Igeta H, Otsuka I, Shibuya M, Egawa J, Sora I, Someya T
  • Journal Title: Psychiatry and Clinical Neurosciences Volume: 印刷中 Issue: 8 Pages: 562-568
  • DOI: 10.1111/pcn.12526
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders (2017)
  • Author(s): Ishizuka K、Fujita Y、Kawabata T、Kimura H、Iwayama Y、Inada T、Okahisa Y、Egawa J、Usami M、Kushima I、Uno Y、Okada T、Ikeda M、Aleksic B、Mori D、Someya To、Yoshikawa T、Iwata N、Nakamura H、Yamashita T、Ozaki N
  • Journal Title: Translational Psychiatry Volume: 7 Issue: 8 Pages: e1184-e1184
  • DOI: 10.1038/tp.2017.173
  • Peer Reviewed / Open Access
• [Journal Article] Rare UNC13B variations and risk of schizophrenia: Whole- exome sequencing in a multiplex family and follow-up resequencing and a case-control study. (2016)
  • Author(s): Egawa J, Hoya S, Watanabe Y, Nunokawa A, Shibuya M, Ikeda M, Inoue E, Okuda S, Kondo K, Saito T, Kaneko N, Muratake T, Igeta H, Iwata N, Someya T
  • Journal Title: American Journal of medical genetics Volume: 14 Issue: 6 Pages: 797-805
  • DOI: 10.1002/ajmg.b.32444
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 自閉症リスク遺伝子Neuroligin3の機能的リン酸化部位の機能解析. (2019)
  • Author(s): 江川純, 五十嵐道弘, 染矢俊幸
  • Organizer: 第115回日本精神神経学会
• [Presentation] Relationship between prefrontal cortex activity during task execution and ADHD symptoms of adult patients, and their changes by atomoxetine. (2018)
  • Author(s): Sugimoto A, Suzuki Y, Yoshinaga K, Orime N, Hayashi T, Egawa J, Ono S, Sugai T, Someya T
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Resequencing of the SETD1A gene in Japanese patients with schizophrenia. (2018)
  • Author(s): Hoya S, Igeta H, Watanabe Y, Nunokawa A, Inoue E, Shibuya M, Egawa J, Someya T
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Rare FBXO18 variations and risk of schizophrenia. (2018)
  • Author(s): Watanabe Y, Hoya S, Hishimoto A, Nunokawa A, Inoue E, Igeta H, Otsuka I, Shibuya M, Sora I, Someya T
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Whole-exome sequencing in a consanguineous multiplex family with schizophrenia and a case-control study. (2018)
  • Author(s): Igeta H, Watanabe Y, Hoya S, Ikeda M, Hishimoto A, Nunokawa A, Inoue E, Sora I, Iwata N, Someya T
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia. (2018)
  • Author(s): Okazaki S, Otsuka I, Watanabe Y, Numata S, Boku S, Shimmyo N, Ohmori T, Someya T, Sora I, Hishimoto A.
  • Organizer: WFSBP Asia Pacific Regional Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Resequencing and association analysis of CLN8 with autism spectrum disorder in a Japanese population. (2016)
  • Author(s): 染矢俊幸
  • Organizer: 22nd World Congress of the International Association for Child and Adolescent Psychiatry and Allied Professions
  • Place of Presentation: Calgary CANADA
  • Year and Date: 2016-09-21
  • Int'l Joint Research
• [Presentation] 自閉スペクトラム症罹患一卵性双生児を含む家系におけるエクソームシークエンスおよびフォローアップ解析. (2016)
  • Author(s): 染矢俊幸
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-09-10
• [Presentation] UNC13B遺伝子の稀な変異と統合失調症の発症リスク. (2016)
  • Author(s): 染矢俊幸
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-09-10
• [Presentation] Rare missense variations and risk of autism: Whole-exome sequencing in affected sib-pair families. (2016)
  • Author(s): 染矢俊幸
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-09-08
  • Invited
• [Presentation] 自閉スペクトラム症におけるCLN8遺伝子のリシークエンスおよび関連解析. (2016)
  • Author(s): 染矢俊幸
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-09-08
• [Presentation] 統合失調症罹患同胞対・両親3家系のエクソーム解析および3段階関連解析. (2016)
  • Author(s): 染矢俊幸
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-09-08