Interaction of AAA chaperones with amyloid fibrils related to human diseases

2013 Fiscal Year Final Research Report

• Project/Area Number: 24659432
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Neurology
• Research Institution: Kumamoto University
• Principal Investigator: OGURA Teru 熊本大学, 発生医学研究所, 教授 (00158825)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: AAA型シャペロン / VCP / 神経変性疾患 / TDP-43 / アミロイド線維 / 高速原子間力顕微鏡

Research Abstract

Amyloid fibrils of TDP-43 accumulate in patients of neurodegenerative diseases caused by mutations in the AAA chaperone VCP. Specific interaction of VCP with TDP-43 amyloid fibrils was demonstrated biochemically and by high-speed atomic force microscopy. Disease-related mutations reduced interaction between VCP and TDP-43 amyloid fibrils. VCP showed a significant disaggregation activity of TDP-43 amyloid fibrils in the presence of ATP. High-speed AFM analysis revealed that the N-D1 ring of CDC-48, a C. elegans VCP homolog, repeatedly rotates clockwise and resets against the D2 ring. A similar result was obtained with human VCP. Based on these observations, we have proposed that repeated back and forward rotations of VCP may account for mechanical force in disaggregation.

Research Products

• [Journal Article] High-speed atomic force microscopic observation of ATP-dependent rotation of the AAA+ chaperone p97 (2013)
  • Author(s): Noi, K., Yamamoto, D., Nishikori, S., Arita-Morioka, K., Kato, T., Ando, T., and Ogura, T.
  • Journal Title: Structure 21 Volume: (Epub) Pages: 1992-2002
  • DOI: 10.1016/j.str.2013.08.017
  • Peer Reviewed
• [Presentation] Dynamics of p97 and the 26S proteasome in action revealed by high-speed atomic force microscopy (2013)
  • Author(s): Ogura, T., Noi, K., Okuno, T., Arita-Morioka, K., Yamamoto, D., Okawa, A., Tsuchiya, H., Saeki, Y., Ando, T., Esaki, M., and Yamanaka, K.
  • Organizer: EMBO Workshop on AAA+ Proteins : from mechanism and disease to targets
  • Place of Presentation: Neuss, Germany
  • Year and Date: 20130915-19
• [Presentation] Functional analysis of disease-associated mutant CDC-48/p97/VCP in C. elegans (2013)
  • Author(s): Yamanaka, K., Murayama, Y., and Ogura, T.
  • Organizer: EMBO Workshop on AAA+ Proteins : from mechanism and disease to targets
  • Place of Presentation: Neuss, Germany
  • Year and Date: 20130915-19
• [Presentation] Biochemical analysis of molecular mechanisms of the interaction between VCP/p97 and amyloid fibrils of TDP-43 (2013)
  • Author(s): Noi, K., Arita-Morioka, K., Ogi, H., Hirao, M., and Ogura, T.
  • Organizer: EMBO Workshop on AAA+ Proteins : from mechanism and disease to targets
  • Place of Presentation: Neuss, Germany
  • Year and Date: 20130915-19
• [Presentation] 分子シャペロンVCP/p97とTDP-43アミロイド線維の相互作用の分子機構の解析 (2013)
  • Author(s): 野井健太郎,有田-森岡健一,小椋光
  • Organizer: 第13回日本蛋白質科学会年会
  • Place of Presentation: 鳥取市、とりぎん文化会館
  • Year and Date: 20130612-14
• [Presentation] AAA chaperones, focusing on the molecular mechanism of p97 (2013)
  • Author(s): Ogura, T., Noi, K., Arita-Morioka, K., Yamamoto, D., Ando, T., Nishikori, S., Esaki, M., and Yamanaka, K.
  • Organizer: EMBO Conference The biology of molecular chaperones : From molecules, organelles and cells to misfolding diseases
  • Place of Presentation: Santa Margherita de Pula, Italy
  • Year and Date: 20130517-22
• [Presentation] 分子シャペロンVCP/p97とTDP-43アミロイド線維の相互作用の分子機構の解析 (2012)
  • Author(s): 野井健太郎,有田-森岡健一,小椋光
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡,マリンメッセ福岡
  • Year and Date: 20121214-16
• [Presentation] High-speed atomic force microscopy of ATP-dependent rotational movements of p97/VCP and its interaction with amyloid fibrils of TDP-43 (2012)
  • Author(s): Noi, K., Yamamoto, D., Arita-Morioka, K., Nishikori, S., Ando, T., and Ogura, T.
  • Organizer: 3rd Kanazawa Bio-AFM Workshop
  • Place of Presentation: 金沢、KKR Hotel Kanazawa
  • Year and Date: 20121105-08
• [Remarks] 熊本大学発生医学研究所分子細胞制御分野のホームページ
  • URL: http://mukb.medic.kumamoto-u.ac.jp/fukusei/index.html
• [Remarks] 熊本大学発生医学研究所分子細胞制御分野AAAホームページ
  • URL: http://mukb.medic.kumamoto-u.ac.jp/AAA/aaainfo.html
• [Remarks] 熊本大学発生医学研究所のホームページ
  • URL: http://www.imeg.kumamoto-u.ac.jp/index.html