The effects of the GPR37-mutation in autism spectrum disorder on the signal transduction by prosaponin

• Project/Area Number: 15K06716
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurophysiology / General neuroscience
• Research Institution: Jichi Medical University
• Principal Investigator: Jimbo Eriko 自治医科大学, 医学部, 講師 (20291651)
• Co-Investigator(Kenkyū-buntansha): 桃井 隆 東京医科大学, 医学部, 客員教授 (40143507)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 自閉性スペクトラム障害 / シナプス接着因子 / GPR37 / CADM1 / 自閉性障害 / シナプス接着蛋白遺伝子

Outline of Final Research Achievements

In the patients with autism spectrum disorder, mutations of various molecules which exist at synapses, have been found. One of them, GPR37 is included in the G protein coupled receptor. However, little is known about the relation with the disease.In this study, it became clear that GPR37 made each complex of NLGN-PSD95 and CADM1-MUPP1, and bound to scaffold proteins via PDZ binding domain. GPR37 is activated by prosaponin. A short sequence prosapotide can substitute the prosaponin. The signaling via prosaptide was reduced in the neurons of GPR37 deficient mice. GPR37 deficient mice showed slight abnormalities in the number of ultrasound vocalization and waveforms by comparison to wild-type mice. In addition, mutations of GPR37L1,
which is highly homologous to GPR37, were also found in autism.

Academic Significance and Societal Importance of the Research Achievements

自閉性スペクトル障害は近年の社会的な問題であり、治療法の確立が求められているが、発達期の脳は多様な要因に対して影響されるため、分子病態の解明が難しい。本研究では、疾患におけるシナプス接着蛋白質とG蛋白質共役型受容体の複合体形成の異常、シグナル伝達系の異常を明らかにしたところに特徴がある。本研究のような機構解明の足掛かりとなる実験の積み重ねが、患者の社会性行動へ効果や治療にあたり、重要性を持つものと考える。

Research Products

• [Journal Article] Aggregate formation analysis of GFAPR416W found in one case of Alexander disease. (2019)
  • Author(s): Tulyeu J, Tamaura M, Jimbo E, Shimbo H, Takano K, Iai M, Yamashita S, Goto T, Aida N, Tokuhiro E, Yamagata T, Osaka H.
  • Journal Title: Brain Dev. Volume: 41 Issue: 2 Pages: 195-200
  • DOI: 10.1016/j.braindev.2018.08.009
  • Peer Reviewed / Open Access
• [Journal Article] Role of a circadian-relevant gene NR1D1 in brain development: possible involvement in the pathophysiology of autism spectrum disorders. (2017)
  • Author(s): Goto, M., Mizuno, M., Matsumoto, A., Yang, Z., Jimbo, E.F., Tabata, H., Yamagata, T., Nagata, K.-I.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 43945-43945
  • DOI: 10.1038/srep43945
  • Peer Reviewed / Open Access
• [Journal Article] Negative feedback loop of bone resorption by NFATc1-dependent induction of Cadm1. (2017)
  • Author(s): Nakamura S, Koyama T, Izawa N, Nomura S, Fujita T, Omata Y, Minami T, Matsumoto M, Nakamura M, Fujita-Jimbo E, Momoi T, Miyamoto T, Aburatani H, Tanaka S.
  • Journal Title: PLoS One. Volume: 12
  • Peer Reviewed / Open Access
• [Journal Article] CASPR2 forms a complex with GPR37 via MUPP1 but not with GPR37(R558Q), an autism spectrum disorder-related mutation. (2015)
  • Author(s): Tanabe Y et al.
  • Journal Title: J Neurochem. Volume: 134 Issue: 4 Pages: 783-793
  • DOI: 10.1111/jnc.13168
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Alterated migration of the neurons with Foxp2(R552H), mutation related to the human speech-language (2018)
  • Author(s): Fujita-jimbo E, Momoi T.
  • Organizer: Neuroscience2018
  • Int'l Joint Research
• [Presentation] CADM1 Mutation Knock-in Mice As Mice Model of ASD Showing Abnormal Excitatory-Inhibitory Synaptic Balance (2017)
  • Author(s): Kojima E. et al.
  • Organizer: International Society for Autism Research (INSAR) 2017
  • Int'l Joint Research
• [Presentation] Role of a Circadian-Relevant Gene; NR1D1; in Brain Development: Possible Involvement in the Pathophysiology of Autism Spectrum Disordeｒ (2017)
  • Author(s): Goto M. et al.
  • Organizer: International Society for Autism Research (INSAR) 2017
  • Int'l Joint Research
• [Presentation] Gene therapy for a mouse model of glucose transporter deficiency syndrome. (2016)
  • Author(s): Nakamura S，Osaka H，Muramatsu S，Takino N，Aoki S， Jimbo E，Shimazaki K，Onaka T，Ohtsuki S，Terasaki T，Yamagata T.
  • Organizer: 第58回 日本小児神経学会学術大会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
• [Presentation] CASPR2 forms a complex with GPR37 via MUPP1 but not with GPR37(R558Q), an autism spectrum disorder-related mutation (2015)
  • Author(s): Tanabe Y, Fujita-Jimbo E, Momoi MY, Momoi T.
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場、神戸国際展示場（神戸）
  • Year and Date: 2015-07-28