Inactivation of prion and amyloid beta proteins by the same RNA and the crosstalk among three components

• Project/Area Number: 18K19397
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: Kyoto University
• Principal Investigator: Katahira Masato 京都大学, エネルギー理工学研究所, 教授 (70211844)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2018: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
• Keywords: プリオンタンパク質 / アミロイドβタンパク質 / RNAアプタマー / 立体構造 / NMR / 相互作用 / Aβタンパク質 / 抗アルツハイマー病 / LTP / アミロイドβ / プリオン / アルツハイマー病 / アプタマー / 構造―機能相関

Outline of Final Research Achievements

We identified an RNA molecule (RNA aptamer) that binds strongly to a normal form of prion protein and thus inhibits the conversion to a pathological abnormal form of the prion protein. The mechanism of this inhibition was elucidated by the structural analysis. Development of in-cell NMR for nucleic acids was also carried out.

Academic Significance and Societal Importance of the Research Achievements

病気との関係が知られているタンパク質の異常型への遷移を、RNA分子によって阻害できる事を示した。また立体構造の解析に基づいて、この阻害メカニズムも合理的に理解する事にも成功した。これらは、RNA分子を薬として活用できる可能性を示す成果である。さらに核酸のインセルNMR法の技術開発によって、ヒトの生細胞中における核酸分子の挙動を直接的に観測する手法が確立された。これは、核酸が関与した基本的な生命現象の理解に役立つ成果である。

Research Products

• [Int'l Joint Research] Gyeongsang National University(韓国)
• [Journal Article] Development and structural determination of an anti-PrPC aptamer that blocks pathological conformational conversion of prion protein (2020)
  • Author(s): Mashima Tsukasa、Lee Joon-Hwa、Kamatari Yuji O.、Hayashi Tomohiko、Nagata Takashi、Nishikawa Fumiko、Nishikawa Satoshi、Kinoshita Masahiro、Kuwata Kazuo、Katahira Masato
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 4934-4934
  • DOI: 10.1038/s41598-020-61966-4
  • NAID: 120006813315
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RNA sequence and length contribute to RNA-induced conformational change of TLS/FUS (2020)
  • Author(s): Hamad Nesreen、Mashima Tsukasa、Yamaoki Yudai、Kondo Keiko、Yoneda Ryoma、Oyoshi Takanori、Kurokawa Riki、Nagata Takashi、Katahira Masato
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 2629-2629
  • DOI: 10.1038/s41598-020-59496-0
  • Peer Reviewed / Open Access
• [Journal Article] Observation of nucleic acids inside living human cells by in-cell NMR spectroscopy (2020)
  • Author(s): Yamaoki Yudai、Nagata Takashi、Sakamoto Tomoki、Katahira Masato
  • Journal Title: Biophysics and Physicobiology Volume: 17 Issue: 0 Pages: 36-41
  • DOI: 10.2142/biophysico.BSJ-2020006
  • NAID: 130007863867
  • ISSN: 2189-4779
  • Peer Reviewed / Open Access
• [Journal Article] Recent progress of in-cell NMR of nucleic acids in living human cells (2020)
  • Author(s): Yamaoki, Y., Nagata, T., Sakamoto, T., and Katahira, M.
  • Journal Title: Biophysical Reviews Volume: - Issue: 2 Pages: 411-417
  • DOI: 10.1007/s12551-020-00664-x
  • Peer Reviewed / Open Access
• [Journal Article] The anti‐prion RNA aptamer R12 disrupts the Alzheimer's disease‐related complex between prion and amyloid β (2019)
  • Author(s): Iida Mamiko、Mashima Tsukasa、Yamaoki Yudai、So Masatomo、Nagata Takashi、Katahira Masato
  • Journal Title: The FEBS Journal Volume: 印刷中 Issue: 12 Pages: 2355-2365
  • DOI: 10.1111/febs.14819
  • Peer Reviewed / Open Access
• [Journal Article] An insight into the dependence of the deamination rate of human APOBEC3F on the length of single-stranded DNA, which is affected by the concentrations of APOBEC3F and single-stranded DNA (2019)
  • Author(s): Wan Li、Kamba Keisuke、Nagata Takashi、Katahira Masato
  • Journal Title: Biochimica et Biophysica Acta (BBA) - General Subjects Volume: In Press Issue: 2 Pages: 129346-129346
  • DOI: 10.1016/j.bbagen.2019.04.011
  • Peer Reviewed / Open Access
• [Journal Article] Mechanism of protein-RNA recognition: analysis based on the statistical mechanics of hydration (2018)
  • Author(s): Hayashi Tomohiko, Matsuda Tomoaki, Nagata Takashi, Katahira Masato, Kinoshita Masahiro
  • Journal Title: Phys Chem Chem Phys Volume: 20 Issue: 14 Pages: 9167-9180
  • DOI: 10.1039/c8cp00155c
  • Peer Reviewed / Open Access
• [Presentation] Unique quadruplex structure and anti-disease activity of RNA aptamer, and in-cell NMR of nucleic acids (2019)
  • Author(s): Katahira, M.
  • Organizer: The 21st Conference of International Society of Magnetic Resonance
  • Int'l Joint Research
• [Presentation] プリオンタンパク質の構造変換を抑制するRNA アプタマーの開発と構造決定 (2019)
  • Author(s): 真嶋司，Lee Joon-Hwa，鎌足雄司，林智彦，永田;崇，西川富美, 西川諭，木下正弘，桑田一夫，片平正人
  • Organizer: 第21回日本RNA学会年会
• [Presentation] 非常に高い活性を有する抗プリオンRNAアプタマーの構造機能相関 (2019)
  • Author(s): 真嶋司，Lee Joon-Hwa，鎌足雄司，林智彦，永田;崇，西川富美, 西川諭，木下正弘，桑田一夫，片平正人
  • Organizer: 第58回NMR討論会
• [Presentation] Disruption of the Alzheimer's disease-related complex betweeen prion and amyloid b by an anti-prion aptamer (2019)
  • Author(s): T. Mashima, M. Iida, Y. Yamaoki, M. So, T. Nagata, M. Katahira
  • Organizer: Commemorative International Symposium of the Japan Society of Nucleic Acids Chemistry (CISNAC)
  • Int'l Joint Research
• [Presentation] Development of anti-prion RNA aptamers and destruction of the Alzheimer's disease-related complex (2019)
  • Author(s): T. Mashima, M. Iida, J.H. Lee, Y. Yamaoki, M. So, Y.O. Kamatari, T. Hayashi, M. Kinoshita, K. Kuwata, T. Nagata, M. Katahira
  • Organizer: International Symposium on Nucleic Acids Chemistry 2019(ISNAC2019)
  • Int'l Joint Research
• [Presentation] Development of RNA Aptamer That Has High Anti-prion Activity and Its Structural Basis (2018)
  • Author(s): Mashima, M., Joon-Hwa, L., Kamatari, Y. O., Hayashi, T., Nishikawa, F., Nagata, T., Nishikawa, S., Kinoshita, M., Kuwata, K. and Katahira, M.
  • Organizer: Japan Society of Nucleic Acids Chemistry
  • Int'l Joint Research
• [Remarks] 片平研究室
  • URL: http://www.iae.kyoto-u.ac.jp/bio/