Transmission mechanism of abnormal conformational transition of polyglutamine protein

2020 Fiscal Year Final Research Report

• Project/Area Number: 17K09755
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Osaka University
• Principal Investigator: Ozawa Daisaku 大阪大学, 医学系研究科, 特任助教 (60554524)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: ポリグルタミン / アミロイド / 神経変性疾患 / プリオン

Outline of Final Research Achievements

Abnormal conformational change of proteins is thought to be a common molecular mechanism of many neurodegenerative diseases. In prion hypothesis, it has been proposed that monomeric misfolded proteins transmit its abnormal structure to native proteins and then form newly misfolded protein monomers. However, the prion hypothesis has not been experimentally proven yet. Moreover, whether the similar phenomenon occurs in other disease-related proteins is unknown. Here, we examined the molecular mechanism of conformational transmission of polyglutamine protein. We revealed that monomeric β-sheet thio-polyQ transmits its β-sheet structure to monomeric α-helix thio-polyQ and then replicates newly monomeric β-sheet thio-polyQ. These results revealed the prion-like conformational transmission between polyglutamine protein monomers, providing experimental evidence for the prion hypothesis. It may be a common phenomenon for neurodegenerative diseases-related proteins.

Free Research Field

蛋白質科学

Academic Significance and Societal Importance of the Research Achievements

本研究による蛋白質のミスフォールディングの実態と異常コンフォメーションの伝播機構の解明は、神経変性疾患で起きうる蛋白質のプリオン現象の共通の分子機構の理解に貢献する。さらに、神経変性疾患の治療・予防法の開発への応用が期待できる。