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2003 Fiscal Year Final Research Report Summary

Molecular analyses of cell death and vacuole formation that are induced by abnormal protein accumulation

Research Project

Project/Area Number 14370057
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

KAKIZUKA Akira  Kyoto Univ.Graduate. School of Biostudies, professor, 大学院・生命科学研究科, 教授 (80204329)

Project Period (FY) 2002 – 2003
Keywordspolyglutamine / vacuole formation / neuronal cell death / AAA ATPase / VCP / amino acid modification / Lewy body / protein aggregates
Research Abstract

In neurodegenerative disorders, protein aggregates and vacuoles are almost universally found in degenerating neurons, suggesting the existence of similar molecular processes in, neuronal cell death. Indeed, 9 inherited neurodegenerative diseases, including Huntington disease have been shown to be caused by the expansion of CAG repeats encoding polyglutamines. We have identified VCP, a member of the AAA ATPase, as a key molecule in neurodegeneration. Namely, 1) VCP co-localizes with polyglutamine aggregates and other protein aggregates such as Lewy bodies in Parkinson disease; 2) Profound deficits in VCP's ATPase activity are found to severely affect ER quality control, leading to abnormal ER expansion and cell death, phenotypes frequently observed in many neurodegenerative diseases; 3) VCP has a potential to unfold misfolded proteins; 4) several amino acid in VCP are modified; 5) Modified VCP shows different ATPase activities. These lines of evidence raise the possibility that excessive accumulation of abnormal proteins may inactivate, VCP's ATPase via its (mis)modification in several neurodegenerative disorders, eventually leading to the neurodegenerations. A proper regulation of VCP function is thus proposed to lead to novel treatments that are effective in a broad spectrum of neurodegenerative diseases.

  • Research Products

    (22 results)

All Other

All Publications (22 results)

  • [Publications] Maeda, H., et al.: "Effective treatment of advanced solid tumors by the combination of Arsenic Trioxide and L-Buthionine-Sulfoximine."Cell Death Differ.. (In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsumoto, M., et al.: "Molecular clearance of ataxin-3 is regulated by a mammalian E4."EMBO J.. 23. 659-669 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kobayashi, T., Kakizuka, A.: "Molecular analyses of Machado-Joseph disease."Cytogenet.Genome Res.. 100. 261-275 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kimura, Y., Kakizuka, A.: "Polyglutamine diseases and molecular chaperones."IUBMB Life. 55. 337-345 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kamei, Y., et al.: "PGC-1β/ERRL1 is an ERR protein ligand, whose expression induces a high-energy expenditure and"Proc.Natl.Acad.Sci.U.S.A.. 100. 12378-12383 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mizuno, Y., et al.: "Vacuole-creating protein in neuro-degenerative diseases."Neurosci.Lett.. 343. 77-80 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Higashiyama, H., et al.: "Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegenerations in Drosophila."Cell Death Differ.. 9. 264-273 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakamoto, M., et al.: "Unequal crossing-over in unique PABP2 Mutations : a possible cause of oculopharyngeal muscular dystrophy."Arch.Neurol.. 59. 474-477 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishitoh, H., et al.: "ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats."Genes & Dev.. 16. 1345-1355 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kimura, Y., et al.: "Circumvention of chaperone requirement for aggregate formation of a short polyglutamine tract by the co-expression of a long polyglutamine tract."J.Biol.Chem.. 277. 37536-37541 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kobayashi, T., et al.: "Functional ATPase activity of p97/VCP is required for the quality control of endoplasmic reticulum in neuronally differentiated mammalian PC12 cells."J.Biol.Chem.. 277. 47358-47365 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Maeda, H., et al.: "Effective treatment of advanced solid tumors by the combination of Arsenic 1Yioxide and L-Buthionine-Sulfoximine."Cell daath Differ.. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsumoto, M., et al.: "Molecular clearance of ataxin-3 is regulated by a mammalian E4."EMBO J.. 23. 659-669 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kobayashi, T., Kakizuka, A.: "Molecular analyses of Machado-Joseph disease."Cytogenet.Genome Res.. 100. 261-275 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kimura, Y, Kakizuka, A.: "Polyglutamine diseases and molecular chaperones."IUBMB Life. 55. 337-345 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kamei, Y., et al.: "PPARg coactivator 1b/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity in mice."Proc.Natl.Acad.Sci.U.S.A.. 100. 12378-12383 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mizuno, Y., et al.: "Vacuole-creating protein in neurodegenerative diseases."Neurosci.Lett.. 343. 77-80 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Higashiyama, H., et al.: "Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegenerations in Drosophila."Cell Death Differ.. 9. 264-273 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakamoto, M., et al.: "Unequal crossing-over, in unique PABP2 Mutations : a possible cause of oculopharyngeal muscular dystrophy."Arch.Neurol.. 59. 474-477 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishitoh, H., et al.: "ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats."Genes & Dev.. 16. 1345-1355 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kimura, Y., et al.: "Circumvention of chaperone requirement for aggregate formation of a short polyglutamine tract by the co-expression of a long polyglutamine tract."J.Biol.Chem.. 277. 37536-37541 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kobayashi, T., et al.: "Functional ATPase activity of p97/VCP is required for the quality control of endoplasmic reticulum in neuronally differentiated mammalian PC12 cells."J.Biol.Chem.. 277. 47358-47365 (2002)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2005-04-19  

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