Interaction of AAA chaperones with amyloid fibrils related to human diseases

• 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
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• 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): K. Noi, D. Yamamoto, S. Nishikori, K. Arita-Morioka, T. Ando, T. Ogura
  • Journal Title: Structure Volume: 21 Issue: 11 Pages: 1992-2002
  • DOI: 10.1016/j.str.2013.08.017
  • Peer Reviewed
• [Journal Article] CDC-48/p97 is required for proper meiotic chromosome segregation via controlling AIR-2/Aurora B kinase localization in Caenorhabditis elegans. (2012)
  • Author(s): Sasagawa Y, Higashitani A, Urano T, Ogura T, Yamanaka K.
  • Journal Title: J Struct Biol. Volume: 179 Issue: 2 Pages: 104-111
  • DOI: 10.1016/j.jsb.2012.06.009
  • Peer Reviewed
• [Journal Article] Caenorhabditis elegans fidgetin homolog FIGL-1, a nuclear-localized AAA ATPase, binds to SUMO. (2012)
  • Author(s): Onitake, A., Yamanaka, K., Esaki, M., and Ogura, T.
  • Journal Title: J. Struct. Biol. Volume: (in press) Issue: 2 Pages: 143-151
  • DOI: 10.1016/j.jsb.2012.04.022
  • Peer Reviewed
• [Journal Article] The C-terminal -helix of SPAS-1, a Caenorhabditis elegans spastin homologue, is crucial for microtubule severing. (2012)
  • Author(s): Onitake, A., Matsushita-Ishiodori, Y., Johjima, A., Esaki, M., Ogura, T., and Yamanaka, K.
  • Journal Title: J. Struct. Biol. Volume: (in press) Issue: 2 Pages: 138-142
  • DOI: 10.1016/j.jsb.2012.04.010
  • Peer Reviewed
• [Journal Article] Cdc48p/p97-mediated regulation of mitochondrial morphology is Vms1p independent. (2012)
  • Author(s): Esaki, M., and Ogura, T.
  • Journal Title: J. Struct. Biol. Volume: (in press) Issue: 2 Pages: 112-120
  • DOI: 10.1016/j.jsb.2012.04.017
  • Peer Reviewed
• [Presentation] Adaptors of p97 and disease-associated p97 mutations. (2014)
  • Author(s): Yamanaka, K., Murayama, Y., and Ogura, T.
  • Organizer: 231st IMEG seminars & Minisymposium
  • Place of Presentation: 熊本市 熊本大学発生医学研究所
• [Presentation] High-speed AFM observation of ATP-dependent rotation of the AAA chaperone p97 and its interaction with TDP-43 amyloid fibrils. (2014)
  • Author(s): Noi, K., Yamamoto, D., Arita-Morioka, K., Ando, T., and Ogura, T.
  • Organizer: 231st IMEG seminars & Minisymposium
  • Place of Presentation: 熊本市 熊本大学発生医学研究所
• [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
• [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
• [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
• [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
• [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
• [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
  • Place of Presentation: Commundo Hotel, Neuss, Germany.
  • Invited
• [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
  • Place of Presentation: Commundo Hotel, Neuss, Germany.
• [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
  • Place of Presentation: Commundo Hotel, Neuss, Germany.
• [Presentation] AAA chaperones, focusing on the molecular mecanism 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
  • Place of Presentation: Santa Margherita de Pula, Italy
  • Invited
• [Presentation] 線虫を用いた疾患型変異CDC-48/p97/VCPの機能解析. (2013)
  • Author(s): 山中 邦俊, 村山 佑樹, 小椋 光
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸市、神戸国際展示場
• [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, 有田ー森岡 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
• [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
• [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
• [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ホテル金沢
• [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・福岡国際会議場、マリンメッセ福岡
• [Book] FtsH protease-mediated regulation of various cellular functions. Subcell. Biochem, 66, Regulated proteolysis in microorganisms. D. A. Dougan (ed.) (2013)
  • Author(s): Okuno, T., and Ogura, T.
  • Total Pages: 17
  • Publisher: Springer
• [Book] FtsH protease. In Handbook of Proteolytic Enzymes, 3rd edition, N. Rawlings and G. Salvesen (ed.) (2013)
  • Author(s): Ogura, T., Okuno, T., Suno, R., and Akiyama, Y.
  • Total Pages: 8
  • Publisher: Elsevier Ltd.
• [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
• [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
• [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