Elucidating of pathogenesis of autism by comprehensive and quantitative analysis of synaptic signaling

• Project/Area Number: 16K21046
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Psychiatric science; Neurochemistry/Neuropharmacology
• Research Institution: Niigata University
• Principal Investigator: Egawa Jun 新潟大学, 医歯学総合研究科, 特任准教授 (80648527)
• Research Collaborator: Igarashi Michihiro
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 自閉スペクトラム症 / NLGN3 / 機能解析 / リン酸化プロテオミクス / シナプス画分 / GAP43 / 機能的リン酸化部位 / 児童思春期精神医学 / 神経生化学

Outline of Final Research Achievements

We selected NLGN3, which are risk genes for autism spectrum disorder (ASD), among genes whose phosphorylation sites are important for neurodevelopment identified by phosphoproteomics of growth cones, and performed functional analysis. 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

ASD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ASD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、ASD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] 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 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 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 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
• [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] 拡散テンソル画像を用いた脳機能結合と自閉スペクトラム症との関連解析 (2019)
  • Author(s): 江川純, 杉本篤言, 吉永清宏, 林剛丞, 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] Resequencing and association analysis of CLN8 with autism spectrum disorder in a Japanese population. (2016)
  • Author(s): 江川純
  • 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): 江川純
  • 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): 江川純
  • 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