Investigation of the folding mechanism of PrPC to PrPSc and assembly of prion agents, and interpretation of the of the beta helix scaffold model

2023 Fiscal Year Final Research Report

• Project/Area Number: 18K06621
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Hagiwara Ken'ichi 国立感染症研究所, 細胞化学部, 主任研究官 (40192265)
• Project Period (FY): 2018-04-01 – 2024-03-31
• Keywords: プリオン / アミロイド / βヘリックス / 蛋白質凝集 / 感染症

Outline of Final Research Achievements

Prion diseases (transmissible spongiform encephalopathies) are fatal neurodegenerative disorders characterized by conformational changes of the normal form of prion protein (PrPC) in neuronal cells to disease-associated form(s) (PrPSc), and cause neuronal degeneration. The structural analysis of PrPSc has been hampered by its insolubility and infectivity, but recent technical advances in the analysis have led to proposal of several intriguing models. The aim of this study was to enhance our understanding of the model structures of PrPSc. Taking the proposed beta-helix model into account, a series of insertional and deletional mutants of PrPC were prepared and their compatibility with the model was examined. The interpretation of the results did not fully support the beta-helix model. The additional outcome was the finding of a truncated mutant that potentially formed proteinase K resistant aggregates.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

PrPScのβヘリックスモデルを念頭に、PrPSc凝集体の構築原理を理解するための研究を進めた。その結果、実験データは想定したβヘリックスモデルに必ずしも合致せず、むしろ、近年解明されつつあるPrPSc以外の蛋白質（シヌクレイン、TDP-43、など）の凝集体構造やPrPScの新たに提唱されているモデルに概して矛盾しないものとなった。想定に反する結果だが、新たな視点が開けた。また、凝集体を形成しやすいPrPC改変体を新たに見い出し、この改変体はPrPScモデル構造研究への応用が期待できる。プリオン病の有効な治療薬の開発は容易ではないが、PrPScの構造研究はその道筋に繋がると考えられる。