Altered molecular interaction between LRR synapse organizer and metabotropic receptors as a core mechanism for neurodevelopmental disorders

• Project/Area Number: 16H04666
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Nagasaki University
• Principal Investigator: ARUGA Jun 長崎大学, 医歯薬学総合研究科(医学系), 教授 (10232076)
• Research Collaborator: YASUDA Hiroki ; NAKAGAWA Shinsuke ; HATAYAMA Minoru
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 神経発達障害 / 多動症 / シナプス伝達 / 疾患モデル動物 / 膜タンパク質 / タンパク質間結合 / 遺伝子変異 / てんかん / タンパク質間相互作用 / タンパク質リン酸化 / シナプス / 発達障害 / シナプス接着分子 / 行動異常 / 脳神経疾患 / 神経科学 / 生体分子 / シグナル伝達 / 薬理学

Outline of Final Research Achievements

In this study, we aimed a better understanding of the disease core mechanism underlying neurodevelopmental disorders including attention-deficit hyperactivity disorder. For this purpose, we focused on the molecular interaction between LRR synapse organizer and metabotropic receptors. Abnormalities appeared in the mice lacking these proteins were analyzed through multidisciplinary approach. As a result, altered synaptic structure and function as well as altered monoaminergic systems that control overall neuronal activities are found to be critically involved in the pathophysiology.

Academic Significance and Societal Importance of the Research Achievements

・研究の対象とした分子機構は申請者らが見いだしたものであり、今回の研究で実験動物を用いて、その生理的意義が明らかになったので、分子レベルでの脳の働きの理解に貢献すると考えられる。
・明らかになった事実は神経発達障害の発症の仕組みの理解、より良い診断法や治療薬の開発に貢献すると予測される。
・解析に用いた遺伝子変異マウスは疾患モデル動物として、さまざまな治療薬の妥当性を評価することに用いられると予測される。

Research Products

• [Journal Article] Identification and characterization of novel conserved domains in metazoan Zic proteins. (2018)
  • Author(s): Tohmonda, T., Kamiya, A., Ishiguro, A., Iwaki, T., Fujimi, T.J., Hatayama, M., Aruga, J.
  • Journal Title: Mol Biol Evol Volume: 35 Issue: 9 Pages: 2205-2229
  • DOI: 10.1093/molbev/msy122
  • Peer Reviewed
• [Journal Article] An Evolutionarily Conserved Mesodermal Enhancer in Vertebrate Zic3. (2018)
  • Author(s): Odaka YS, Tohmonda T, Toyoda A, Aruga J.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 14954-14954
  • DOI: 10.1038/s41598-018-33235-y
  • Peer Reviewed / Open Access
• [Journal Article] Link between the causative genes of holoprosencephaly: Zic2 directly regulates Tgif1 expression. (2018)
  • Author(s): Ishiguro A, Hatayama M, Otsuka MI, Aruga J
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 2140-2140
  • DOI: 10.1038/s41598-018-20242-2
  • Peer Reviewed / Open Access
• [Journal Article] LRRシナプスオーガナイザーと神経発達障害 (2018)
  • Author(s): 有賀 純
  • Journal Title: BIO INDUSTRY Volume: 35 Pages: 24-33
• [Journal Article] Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice (2017)
  • Author(s): Morimura Naoko、Yasuda Hiroki、Yamaguchi Kazuhiko、Katayama Kei-ichi、Hatayama Minoru、Tomioka Naoko H.、Odagawa Maya、Kamiya Akiko、Iwayama Yoshimi、Maekawa Motoko、Nakamura Kazuhiko、Matsuzaki Hideo、Tsujii Masatsugu、Yamada Kazuyuki、Yoshikawa Takeo、Aruga Jun
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 15800-15800
  • DOI: 10.1038/ncomms15800
  • Peer Reviewed / Open Access
• [Journal Article] Autism-like behaviors and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice (2017)
  • Author(s): Morimura, N., Yasuda, H., Yamaguchi K., Katayama, K., Hatayama, M., Tomioka, N.H., Odagawa, M., Kamiya, A., Iwayama, Y., Maekawa, M., Nakamura, K., Matsuzaki, H., Tsujii, M., Yamada, K., Yoshikawa, T., Aruga, J.
  • Journal Title: Nature Communications Volume: 印刷中
  • NAID: 130007901310
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Role of Lrrn3, a brain-enriched transmembrane protein in neural development. (2018)
  • Author(s): Nakamura M, Hatayama M, Nakagawa S, Aruga J.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Altered monoamine dynamics and abnormal behaviors in Lrtm2-deficient mice. (2018)
  • Author(s): Ichise M, Katayama K, Sakoori K, Morimura N, Hatayama M, Aruga J.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Autism-like behaviors and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice. (2018)
  • Author(s): Morimura N, Yasuda H, Katayama K, Hatayama M, Yoshikawa T, Aruga J.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Roles of sphingosine-1 phosphate in blood-brain barrier using in vitro and in vivo ischemia reperfusion injury model. (2018)
  • Author(s): Nakagawa S, Aruga J.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] LRR膜タンパク質ファミリーによるシナプス制御とその破綻による病態 (2017)
  • Author(s): 有賀 純
  • Organizer: 第122回日本解剖学会全国学術集会
  • Place of Presentation: 長崎大学坂本キャンパス（長崎県長崎市）
  • Year and Date: 2017-03-28
  • Invited
• [Presentation] てんかん・多動症患者に見られたElfn1変異体の分子機能解析 (2017)
  • Author(s): 織方良介、牧野まどか、畑山 実、有賀 純
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール（長崎県長崎市）
  • Year and Date: 2017-03-15
• [Presentation] Elfn2欠損マウスに見られる代謝異常 (2017)
  • Author(s): 牧野まどか、富岡直子、有賀 純
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール（長崎県長崎市）
  • Year and Date: 2017-03-15
• [Presentation] Slitrk1 regulates adrenergic innervation in prefrontal cortex (PFC) and affects anxiety/depression related behavior (2017)
  • Author(s): Hatayama M, Katayama K, Takashima N, Aruga J.
  • Organizer: 第40回日本神経科学大会
• [Presentation] Elfn2欠損マウスに見られる代謝異常症 (2017)
  • Author(s): 牧野 まどか、富岡 直子、松永 隼人、有賀 純
  • Organizer: 第70回日本薬理学会西南部会
• [Book] Zic family - Evolution, Development and Disease. (2018)
  • Author(s): Aruga J
  • Total Pages: 380
  • Publisher: Springer Nature
  • ISBN: 9789811073106
• [Remarks] 発達障害と社会的行動障害に関わるシナプス成熟促進タンパク質の発見
  • URL: http://www.med.nagasaki-u.ac.jp/phrmch1/ra-nmor2017.html