Mechanism of epilepsy pathogenesis and search for preventive drugs

• Project/Area Number: 17K07126
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: Taya Shinichiro 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 病態生化学研究部, 室長 (60362232)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: てんかん / 神経回路網 / 抗てんかん薬 / 薬理学的シャペロン / 脳神経疾患 / 脳・神経 / 神経科学

Outline of Final Research Achievements

The pathogenesis of epilepsy is poorly understood and good diagnostic and therapeutic methods have not yet been established. Previously, we identified DSCAML1 as a responsible gene in rats with spontaneous epilepsy. In the present study, we analyzed the DSCAML1 gene in human epilepsy patients and identified several SNPs that cause missense mutations. Furthermore, we generated patient-type DSCAML1 knock-in mice and detected abnormal brain waves. These results suggest that loss of function of DSCAML1 may be involved in the development of epilepsy.

Academic Significance and Societal Importance of the Research Achievements

国内外で、てんかんの病態解明を目指している研究は他にも多々なされている。これまでに、てんかんをはじめとする精神・神経疾患の分野では遺伝学的・細胞生物学的な解析はなされてきた。しかし、本研究のようにてんかんに直接関連する分子に直接結合する分子群をプロテオームの手法を用いて同定し解析することはほとんどされてはいない。また、我が国に患者数が百万人以上いると言われるてんかんであるが、本研究によってその病態が理解され、さらに新たな診断法や治療法が開発されれば、大きく国民の生活の向上に貢献するであろうと信じている。

Research Products

• [Journal Article] Potential involvement of DSCAML1 mutations in neurodevelopmental disorders (2021)
  • Author(s): Ogata S, Hashizume K, Hayase Y, Kanno Y, Hori K, Balan S, Yoshikawa T, Takahashi H, Taya S, Hoshino M
  • Journal Title: Genes Cells Volume: (3) Issue: 3 Pages: 136-151
  • DOI: 10.1111/gtc.12831
  • Peer Reviewed / Open Access
• [Journal Article] Down syndrome cell adhesion molecule like-1 (DSCAML1) links the GABA system and seizure susceptibility. (2020)
  • Author(s): Hayase Y, Amano S, Hashizume K, Tominaga T, Miyamoto H, Kanno Y, Ueno-Inoue Y, Inoue T, Yamada M, Ogata S, Balan S, Hayashi K, Miura Y, Tokudome K, Ohno Y, Nishijo T, Momiyama T, Yanagawa Y, Takizawa A, Mashimo T, Serikawa T, Sekine A, Nakagawa E, Takeshita E, Yoshikawa T, Waga C, Inoue K, Goto YI, Nabeshima Y, et al.
  • Journal Title: Acta Neuropathol Commun. Volume: 8 Issue: 1 Pages: 206-206
  • DOI: 10.1186/s40478-020-01082-6
  • Peer Reviewed / Open Access
• [Journal Article] The role of SCFSkp2 and SCFβ-TrCP1/2 in the cerebellar granule cell precursors (2020)
  • Author(s): Yamashita M, Owa T, Shiraishi R, Adachi T, Ichijo K, Taya S, Miyashita S, Hoshino M
  • Journal Title: Genes Cells Volume: (12) Issue: 12 Pages: 796-810
  • DOI: 10.1111/gtc.12813
  • Peer Reviewed / Open Access
• [Journal Article] DSCAM regulates delamination of neurons in the developing midbrain (2020)
  • Author(s): Arimura Nariko、Okada Mako、Taya Shinichiro、Dewa Ken-ichi、Tsuzuki Akiko、Uetake Hirotomo、Miyashita Satoshi、Hashizume Koichi、Shimaoka Kazumi、Egusa Saki、Nishioka Tomoki、Yanagawa Yuchio、Yamakawa Kazuhiro、Inoue Yukiko U.、Inoue Takayoshi、Kaibuchi Kozo、Hoshino Mikio
  • Journal Title: Science Advances Volume: 6 Issue: 36 Pages: 1693-1693
  • DOI: 10.1126/sciadv.aba1693
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive and cell-type-based characterization of the dorsal midbrain during development (2018)
  • Author(s): Arimura Nariko、Dewa Ken-ichi、Okada Mako、Yanagawa Yuchio、Taya Shin-ichiro、Hoshino Mikio
  • Journal Title: Genes to Cells Volume: 24 Issue: 1 Pages: 41-59
  • DOI: 10.1111/gtc.12656
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Meis1 Coordinates Cerebellar Granule Cell Development by Regulating Pax6 Transcription, BMP Signaling and Atoh1 Degradation (2018)
  • Author(s): Owa Tomoo、Taya Shinichiro、Miyashita Satoshi、Yamashita Mariko、Adachi Toma、Yamada Koyo、Yokoyama Miwa、Aida Shogo、Nishioka Tomoki、Inoue Yukiko U.、Goitsuka Ryo、Nakamura Takuro、Inoue Takayoshi、Kaibuchi Kozo、Hoshino Mikio
  • Journal Title: The Journal of Neuroscience Volume: 38 Issue: 5 Pages: 1277-1294
  • DOI: 10.1523/jneurosci.1545-17.2017
  • Peer Reviewed / Open Access / Int'l Joint Research