Transmission mechanism of abnormal conformational transition of polyglutamine protein

• 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
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ポリグルタミン / アミロイド / 神経変性疾患 / プリオン / ポリグルタミン蛋白質

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.

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。

Research Products

• [Journal Article] Arginine is a disease modifier for polyQ disease models that stabilizes polyQ protein conformation. (2020)
  • Author(s): Minakawa EN, Popiel HA, Tada M, Takahashi T, Yamane H, Saitoh Y, Takahashi Y, Ozawa D, Takeda A, Takeuchi T, Okamoto Y, Yamamoto K, Suzuki M, Fujita H, Ito C, Yagihara H, Saito Y, Watase K, Adachi H, Katsuno M, Mochizuki H, Shiraki K, Sobue G, Toda T, Wada K, Onodera O, Nagai Y.
  • Journal Title: Brain Volume: 143 Issue: 6 Pages: 1811-1825
  • DOI: 10.1093/brain/awaa115
  • Peer Reviewed
• [Presentation] ポリグルタミン蛋白質におけるプリオン様異常構造伝播機構 (2020)
  • Author(s): 小澤大作、武内敏秀、永井義隆
  • Organizer: 第18回 神経科学研究会
• [Presentation] ポリグルタミン蛋白質によるプリオン様異常構造伝播 (2019)
  • Author(s): 小澤大作、武内敏秀、永井義隆
  • Organizer: 第７回アミロイドーシス学会学術集会
• [Presentation] ポリグルタミン蛋白質による異常構造伝播 (2019)
  • Author(s): 小澤大作、永井義隆
  • Organizer: 大阪大学蛋白質研究所セミナー
  • Invited
• [Presentation] Conformational transmission between polyglutamine protein monomers (2019)
  • Author(s): Daisaku Ozawa, Toshihide Takeuchi, Yoshitaka Nagai
  • Organizer: Asian Pacific Prion Symposium 2019
  • Int'l Joint Research
• [Presentation] ポリグルタミン蛋白質によるプリオン様異常構造伝播 (2019)
  • Author(s): 小澤大作、武内敏秀、永井義隆
  • Organizer: 第１４回日本臨床ストレス応答学会大会
• [Presentation] 神経変性疾患と液-液相分離 (2019)
  • Author(s): 小澤大作、永井義隆
  • Organizer: 第２回LLPS研究会
• [Presentation] Prion-like conformational transmission of polyglutamine protein (2019)
  • Author(s): Daisaku Ozawa, Toshihide Takeuchi, Yoshitaka Nagai
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] ポリグルタミン蛋白質による異常構造伝播機構の解明 (2018)
  • Author(s): 小澤大作、武内敏秀、永井義隆
  • Organizer: 第１８回日本蛋白質科学会年会
• [Book] 相分離生物学の全貌 (2020)
  • Author(s): 小澤大作、永井義隆
  • Total Pages: 416
  • Publisher: 東京化学同人
  • ISBN: 9784807913466
• [Book] タンパク質のアモルファス凝集と溶解性 (2019)
  • Author(s): 小澤大作、武内敏秀、永井義隆
  • Total Pages: 283
  • Publisher: シーエムシー出版
  • ISBN: 9784781313979