Analysis of the centrosome function via CAMDI and higher brain function during stress in CAMDI knockout mice

• Project/Area Number: 17K08793
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Fukuda Toshifumi 東京薬科大学, 生命科学部, 講師 (50372313)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: CAMDI / 記憶 / 学習 / KIBRA / 中心体 / 移動 / dilation / 自閉症 / AMPA / ストレス / PTSD / AMPA受容体 / 記憶・学習 / ドラッグリポジショニング

Outline of Final Research Achievements

KIBRA was identified as a novel CAMDI-binding protein that retains AMPAR in the cytosol after internalization. KIBRA inhibited CAMDI-dependent Rab11 activation, thereby attenuating AMPAR cell surface expression. Knockdown of CAMDI in hippocampal neurons increased the amount of internalized alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) and attenuated the chemical long-term potentiation (LTP)-dependent cell surface expression of AMPAR. CAMDI-deficient mice exhibited impaired recognition memory and spatial reference memory.
In migrating cortical neurons, CAMDI was localized at a structure, called dilation, with the centrosome. In dilation, it became clear that the oscillation of EGFP-CAMDI stable-unstable states was repeatedly during cortical migration.

Academic Significance and Societal Importance of the Research Achievements

自閉症などの発達障害は、幼児期や学童期はもちろん、「大人の発達障害」と呼ばれるように、日常生活に大きな支障をきたし社会的な問題となっている。しかしその根本的な発症要因は未だ解明されていない。そのため、治療や対処法に関しても統一的な解釈がなく、患者数、治療費などによる社会的な損失は計り知れない。
大脳皮質発生過程はマウスとヒトにおいて共通する分子メカニズムがあると考えられている。本研究は自閉症を含む精神疾患の病理と分子メカニズムの解明、将来的には精神疾患の予防、治療へとつながると考えており、その基礎研究として貢献できると考えている。

Research Products

• [Journal Article] CAMDI interacts with the human memory-associated protein KIBRA and regulates AMPAR cell surface expression and cognition (2019)
  • Author(s): Fukuda Toshifumi、Nagashima Shun、Inatome Ryoko、Yanagi Shigeru
  • Journal Title: PLOS ONE Volume: 14 Issue: 11 Pages: e0224967-e0224967
  • DOI: 10.1371/journal.pone.0224967
  • Peer Reviewed / Open Access
• [Journal Article] Critical role of CRAG, a splicing variant of centaurin-γ3/AGAP3, in ELK1-dependent SRF activation at PML bodies. (2019)
  • Author(s): Nagashima S, Takeda K, Shiiba I, Higashi M, Fukuda T, Tokuyama T, Matsushita N, Nagano S, Araki T, Kaneko M, Shioi G, Inatome R, Yanagi S.
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 20107-20107
  • DOI: 10.1038/s41598-019-56559-9
  • Peer Reviewed / Open Access
• [Journal Article] MITOL deletion in the brain impairs mitochondrial structure and ER tethering leading to oxidative stress (2019)
  • Author(s): Nagashima Shun、Takeda Keisuke、Ohno Nobuhiko、Ishido Satoshi、Aoki Motohide、Saitoh Yurika、Takada Takumi、Tokuyama Takeshi、Sugiura Ayumu、Fukuda Toshifumi、Matsushita Nobuko、Inatome Ryoko、Yanagi Shigeru
  • Journal Title: Life Science Alliance Volume: 2 Issue: 4 Pages: e201900308-e201900308
  • DOI: 10.26508/lsa.201900308
  • Peer Reviewed / Open Access
• [Journal Article] MITOL prevemts ER stress-induced apoptosis by IRE1 ubiquitylation at mitochondrial-ER contact sites. (2019)
  • Author(s): Takeda, K., Nagashima, S., Shiiba, I., Uda, A., Tokuyama, T., Ito, N., Fukuda, T., Matsushita, N., Ishido, S., Iwawaki, T., Uehara, T., Inatome, R., and Yanagi, S.
  • Journal Title: EMBO J. Volume: 38 Issue: 15
  • DOI: 10.15252/embj.2018100999
  • Peer Reviewed / Open Access
• [Journal Article] Psychiatric behaviors associated with cytoskeletal defects in radial neuronal migration. (2017)
  • Author(s): Fukuda T, Yanagi S
  • Journal Title: Cellular and molecular life sciences Volume: 74 Issue: 19 Pages: 3533-3552
  • DOI: 10.1007/s00018-017-2539-4
  • Peer Reviewed
• [Presentation] CAMDIの動態を介した神経細胞移動とネットワーク形成 (2019)
  • Author(s): 福田敏史
  • Organizer: 第42回 日本分子生物学会年会
  • Invited
• [Presentation] 神経細胞移動における精神疾患関連タンパク質CAMDIと Wnt/β-cateninシグナルとの関連 (2018)
  • Author(s): 加藤 冴穗 , 福田 敏史 , 矢部 麻奈 , 鈴木 千香子 , 丸田 義也 , 吉原 惇完 佐藤 志保 , 佐藤 瑞月, 稲留 涼子 , 柳 茂
  • Organizer: 日本分子生物学会
• [Presentation] HDAC6特異的阻害剤によるCAMDI欠損マウスの細胞移動障害と自閉症様行動の回復 (2017)
  • Author(s): 福田敏史、稲留涼子、柳茂
  • Organizer: 日本神経科学学会（Neuroscience2017）
• [Presentation] CAMDI欠損マウスのHDAC6特異的阻害剤による大脳皮質神経細胞の移動異常と自閉症様行動の回復 (2017)
  • Author(s): 福田敏史
  • Organizer: 日本分子生物学会（生命科学系学会合同年次大会、ConBio2017）