Construction of prion disease model using neuroblastoma cells and elucidation of the production mechanism of abnormal prion protein

• Project/Area Number: 18K07499
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: The University of Tokushima
• Principal Investigator: HARA Hideyuki 徳島大学, 先端酵素学研究所(次世代), 助教 (40469953)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: プリオン / プリオン病 / ウイルス / ウイルス感染 / 神経変性 / 構造変換 / 異常型

Outline of Final Research Achievements

Prion disease is a neurodegenerative disease in which normal prion protein expressed in healthy nerve tissues undergoes conformational conversion into an infectious, protease K resistant, abnormal prion protein that accumulates in the central nervous system. Idiopathic prion diseases, which account for about 77% of all human prion diseases, occur in one out of one million people each year, but their etiology　are unknown and there is no cure. In this study, we infected mouse neurons with neuropathogenic influenza A virus (IAV) in the hope that IAV infection could conformational conversion from normal prion protein into abnormal prion protein. As a result, we found that the normal prion protein undergoes conformational conversion into the abnormal prion protein.

Academic Significance and Societal Importance of the Research Achievements

プリオン病は、病因が不明で治療法も存在しない希少疾患であるが、潜在的リスク保有者が多数おり、治療・予防法の確立が求められている。神経細胞にIAVを感染することで、正常型プリオンが異常型プリオンへと構造変換するという研究代表者の発見は、これまで不明だったプリオン病発症のトリガー因子としてIAV感染が関与している可能性を強く示しており、プリオン病の病因解明に新たな指針を与える。また、アルツハイマー病やパーキンソン病といった、蛋白質凝集体の蓄積が原因の神経変性疾患でも、ウイルス感染が凝集体形成のきっかけになる可能性が示唆されており、神経変性疾患全般の治療・予防に向けたフィードバックも可能となる。

Research Products

• [Journal Article] Vaporized Hydrogen Peroxide and Ozone Gas Synergistically Reduce Prion Infectivity on Stainless Steel Wire (2021)
  • Author(s): Hara Hideyuki、Chida Junji、Pasiana Agriani Dini、Uchiyama Keiji、Kikuchi Yutaka、Naito Tomoko、Takahashi Yuichi、Yamamura Junji、Kuromatsu Hisashi、Sakaguchi Suehiro
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 6 Pages: 3268-3268
  • DOI: 10.3390/ijms22063268
  • NAID: 120007164927
  • Peer Reviewed / Open Access
• [Journal Article] Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91?106 (2020)
  • Author(s): Uchiyama Keiji、Miyata Hironori、Yamaguchi Yoshitaka、Imamura Morikazu、Okazaki Mariya、Pasiana Agriani Dini、Chida Junji、Hara Hideyuki、Atarashi Ryuichiro、Watanabe Hitomi、Kondoh Gen、Sakaguchi Suehiro
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 19 Pages: 7260-7260
  • DOI: 10.3390/ijms21197260
  • NAID: 120006959718
  • Peer Reviewed / Open Access
• [Journal Article] N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases (2020)
  • Author(s): Hara Hideyuki、Sakaguchi Suehiro
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 17 Pages: 6233-6233
  • DOI: 10.3390/ijms21176233
  • NAID: 120006959719
  • Peer Reviewed / Open Access
• [Journal Article] Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice (2020)
  • Author(s): Chida Junji、Hara Hideyuki、Uchiyama Keiji、Takahashi Etsuhisa、Miyata Hironori、Kosako Hidetaka、Tomioka Yukiko、Ito Toshihiro、Horiuchi Hiroyuki、Matsuda Haruo、Kido Hiroshi、Sakaguchi Suehiro
  • Journal Title: PLOS Pathogens Volume: 16 Issue: 8 Pages: e1008823-e1008823
  • DOI: 10.1371/journal.ppat.1008823
  • NAID: 120006956844
  • Peer Reviewed / Open Access
• [Journal Article] The N-Terminal Polybasic Region of Prion Protein Is Crucial in Prion Pathogenesis Independently of the Octapeptide Repeat Region (2020)
  • Author(s): †Das Rani Nandita, †Miyata Hironori, †Hara Hideyuki, Chida Junji, Uchiyama Keiji, Masujin Kentaro, Watanabe Hitomi, Kondoh Gen, Sakaguchi Suehiro, †equally contribution
  • Journal Title: Mol Neurobiol. Volume: 57 Issue: 2 Pages: 1203-1216
  • DOI: 10.1007/s12035-019-01804-5
  • Peer Reviewed
• [Journal Article] Tracking and clarifying differential traits of classical- and atypical L-type bovine spongiform encephalopathy prions after transmission from cattle to cynomolgus monkeys (2019)
  • Author(s): Hagiwara Ken’ichi、Sato Yuko、Yamakawa Yoshio、Hara Hideyuki、Tobiume Minoru、Okemoto-Nakamura Yuko、Sata Tetsutaro、Horiuchi Motohiro、Shibata Hiroaki、Ono Fumiko
  • Journal Title: PLOS ONE Volume: 14 Issue: 5 Pages: e0216807-e0216807
  • DOI: 10.1371/journal.pone.0216807
  • Peer Reviewed / Open Access
• [Journal Article] Prion protein protects mice from lethal infection with influenza A viruses (2018)
  • Author(s): Chida Junji、Hara Hideyuki、Yano Masashi、Uchiyama Keiji、Das Nandita Rani、Takahashi Etsuhisa、Miyata Hironori、Tomioka Yukiko、Ito Toshihiro、Kido Hiroshi、Sakaguchi Suehiro
  • Journal Title: PLOS Pathogens Volume: 14 Issue: 5 Pages: e1007049-e1007049
  • DOI: 10.1371/journal.ppat.1007049
  • NAID: 120006524496
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ウイルス感染を用いたプリオン病発症機構の解明 (2019)
  • Author(s): 原 英之、千田 淳司、坂口 末廣
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] インフルエンザウイルス感染は神経細胞において異常型プリオン産生のトリガーとなる (2018)
  • Author(s): 原 英之、千田 淳司、坂口 末廣
  • Organizer: 第41回日本分子生物学会年会
• [Book] ブレインサイエンス・レビュー2021 (2021)
  • Author(s): 廣川 信隆、板東 武彦／編、原 英之／9章を分担執筆
  • Total Pages: 240
  • Publisher: アドスリー
  • ISBN: 9784904419991