Chemical Biology for Parkinson's disease

• Project/Area Number: 18H02099
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
• Research Institution: Juntendo University (2020); Keio University (2018-2019)
• Principal Investigator: Imoto Masaya 順天堂大学, 医学(系)研究科(研究院), 特任教授 (60213253)
• Co-Investigator(Kenkyū-buntansha): 斉木 臣二 順天堂大学, 医学部, 准教授 (00339996) ; 野田 展生 公益財団法人微生物化学研究会, 微生物化学研究所, 部長 (40396297)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2018: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: パーキンソン疾患 / オートファジー / メタボローム 解析 / 神経変性疾患 / タンパク質凝集 / 相分離 / パーキンソン / アグリソーム / ビリルビン / 凝集タンパク質 / パーキンソン病 / パーキンソン症 / バイオマーカー / ケミカルバイオロジー

Outline of Final Research Achievements

We have conducted mechanism studies of three Parkinson’s disease (PD) drug-seeds, which were obtained by the screening for metabolome analysis of PD and for clearance of protein aggregation seen in the brain of PD patients. We found that they function by targeting inhibition of Keap1-Nrf2 binding, activation of PLC -mediated TFEB transcription activity, and stimulation of liquid-liquid phase separation of target protein, respectively, thereby showing neuro-protection in PD-model neuronal cells.

Academic Significance and Societal Importance of the Research Achievements

PDのメタボローム解析研究の成果から，治療薬シードの発見および作用機構解析を行ったことでメタボローム 解析研究がバイオマーカー探索だけでなく直接創薬研究に展開できることを示した．また，ケミカルバイオロジーの手法でタンパク質凝集をクリアランスする新しいメカニズムを提唱することができ，このことは他の神経変性疾患の創薬研究にも応用できる可能性を持つ重要性を有している．

Research Products

• [Journal Article] A chemical genomics-aggrephagy integrated method studying functional analysis of autophagy inducers (2020)
  • Author(s): Kataura Tetsushi、Tashiro Etsu、Nishikawa Shota、Shibahara Kensuke、Muraoka Yoshihito、Miura Masahiro、Sakai Shun、Katoh Naohiro、Totsuka Misato、Onodera Masafumi、Shin-Ya Kazuo、Miyamoto Kengo、Sasazawa Yukiko、Hattori Nobutaka、Saiki Shinji、Imoto Masaya
  • Journal Title: Autophagy Volume: Aug 7 Issue: 8 Pages: 1-17
  • DOI: 10.1080/15548627.2020.1794590
  • Peer Reviewed / Open Access
• [Journal Article] Miclxin, a novel MIC60 inhibitor, induces apoptosis via mitochondrial stress in β-catenin mutant tumor cells. (2020)
  • Author(s): 20)Ikeda, H., Muroi, M., Kondoh, Y., Ishikawa, S., Kakeya, H., Osada, H., Imoto, M.
  • Journal Title: ACS Chem. Biol. Volume: 15 Issue: 8 Pages: 2195-2204
  • DOI: 10.1021/acschembio.0c00381
  • Peer Reviewed / Open Access
• [Journal Article] BRUP-1, an intracellular bilirubin modulator, exerts neuroprotective activity in a cellular Parkinson’s disease model. (2020)
  • Author(s): Kataura, T., Saiki, S., Ishikawa, K., Akamatsu, W., Sasazawa, Y., Hattori, N., Imoto, M.
  • Journal Title: J. Neurochemstry Volume: - Issue: 1 Pages: 81-97
  • DOI: 10.1111/jnc.14997
  • Peer Reviewed / Open Access
• [Journal Article] Discovery of “heat shock metabolites” produced by thermotolerant actinomycetes in high-temperature culture. (2020)
  • Author(s): Saito, S., Kato, W., Ikeda, H., Katsuyama, Y., Ohnishi, Y., Imoto, M.
  • Journal Title: J. Antibiot. Volume: 73 Issue: 4 Pages: 203-210
  • DOI: 10.1038/s41429-020-0279-4
  • Peer Reviewed / Open Access
• [Journal Article] CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobacter pylori CagA-degraded autophagy (2019)
  • Author(s): Tsugawa H., Mori H., Matsuzaki J., Sato A., Saito Y., Imoto M., Suematsu M., Suzuki H.
  • Journal Title: Autophagy Volume: 15 Issue: 2 Pages: 242-258
  • DOI: 10.1080/15548627.2018.1515530
  • Peer Reviewed / Open Access
• [Journal Article] 14-3-3εa directs the pulsatile transport of basal factors towards the apical domain for lumen growth in tubulogenesis. (2018)
  • Author(s): Yuji Mizotani, Mayu Suzuki, Kohji Hotta, Hidenori Watanabe, Kogiku Shiba, Kazuo Inaba, Etsu Tashiro, Kotaro Oka, Masaya Imoto
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 115 Issue: 38
  • DOI: 10.1073/pnas.1808756115
  • NAID: 120007133686
  • Peer Reviewed / Open Access
• [Journal Article] Identification of protein kinase C isozymes involved in the anti-proliferative and pro-apoptotic activities of 10-Methyl-aplog-1, a simplified analog of debromoaplysiatoxin, in several cancer cell lines (2018)
  • Author(s): Yusuke Hanaki, Yuki Shikata, Masayuki Kikumori, Natsuki Hotta, Masaya Imoto, Kazuhiro Irie
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 495 Issue: 1 Pages: 438-445
  • DOI: 10.1016/j.bbrc.2017.11.052
  • Peer Reviewed / Open Access
• [Presentation] Formycin Aによる去勢抵抗性前立腺がん細胞選択的細胞死誘導 (2020)
  • Author(s): 武井 智暉, 濱村 祐輝, 本郷 周, 小坂 威雄, 大家 基嗣, 井本 正哉
  • Organizer: 日本がん分子標的治療学会
• [Presentation] Formycin A selectively induced apoptosis in castration-resistant prostate cancer (2019)
  • Author(s): Masaya Imoto, Hiroshi Hongo, Takeo Kosaka, Mototsugu Oya
  • Organizer: 日本癌学会
• [Presentation] ケミカルバイオロジーで挑むホヤの脊索管形成機構解析 (2019)
  • Author(s): Masaya Imoto
  • Organizer: 先端モデル動物支援プラットフォーム成果発表会2018
  • Invited
• [Presentation] バイオマーカーを指標とするパーキンソン病治療薬の探索とBET阻害剤JQ1による神経保護活性 (2018)
  • Author(s): 片浦哲志、斉木臣二、服部信孝、井本正哉
  • Organizer: 日本ケミカルバイオロジー学会 第13回年会
• [Presentation] Biomarker-based Screening Identified BET inhibitor JQ1 as a Neuroprotective Compound for Parkinson’s Disease (2018)
  • Author(s): Tetsushi Kataura, Shinji Saiki, Nobutaka Hattori, Masaya Imoto
  • Organizer: 第9回日韓ケミカルバイオロジーシンポジウム
  • Int'l Joint Research
• [Presentation] がん細胞の特性を標的とする阻害剤の化学生物学的研究 (2018)
  • Author(s): 井本正哉
  • Organizer: 日本農芸化学会 2018年度第1回 関東支部例会
  • Invited
• [Presentation] Chemical genomic analysis on autophagic regulation mechanism in human lung cancer A549 cells (2018)
  • Author(s): T. Kataura, M. Imoto
  • Organizer: EORTC NCI AACR 2018
  • Int'l Joint Research