• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Screening of compounds for protecting polyglutamine diseases

Research Project

Project/Area Number 13557058
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Neurology
Research InstitutionRIKEN

Principal Investigator

NUKINA Nobuyuki  RIKEN, Molecular Neuropathology Group, Group Director, 病因遺伝子研究グループ, グループディレクター (10134595)

Co-Investigator(Kenkyū-buntansha) TANAKA Motomasa  RIKEN, Lab. for Structural Neuropathology, Research Scientist, 構造神経病理研究チーム, 研究員 (40321781)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥12,000,000 (Direct Cost: ¥12,000,000)
Fiscal Year 2002: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2001: ¥8,000,000 (Direct Cost: ¥8,000,000)
KeywordsPolyglutamine / CAG repeat / Aggregate / Cell death / Myoglobin
Research Abstract

A major hallmark of the polyglutamine (pQ) diseases is the formation of pQ inclusions. Recently, misfolding has come to be considered one of the primary factors for pQ protein aggregation, although, the nature of misfolding and the relationship between misfolding and ubiquitination of the expanded pQ protein is not yet known. By using ataxin-3, the defective gene product of SCA3/MJD, we demonstrated that the cellular toxicity of a pQ protein is directly proportional to the length of the glutamine repeats and inversely dependent on the size of the corresponding protein. The pQ expansion and truncation enhance the reactivity of 1C2 antibody (specific to expanded pQ), chaperone association and ubiquitination, suggesting that pQ expansion and protein truncation enhance the protein misfolding.
The protein misfolding induced by pQ expansion was further investigated with our molecular model system using mutant myoglobin which is inserted different size of pQ. Polyglutamine stretches form intra … More molecular β-sheets when pQ expanded and they form intermolecular β-sheets and amyloid fibrils after certain incubation time. The surface of the mutant myoglobin with expanded pQ was partially unfolded and destabilized. We also investigated the early phase of fibrillization of the mutant myoglobin in which 35 or 50 glutamine repeats are inserted. Small-angle X-ray scattering and electron microscopic studies revealed that the expansion of pQ to 50 repeats induced the formation of quasi-aggregate in the earliest stage of the protein fibrillization. We found that β-sheets of pQ in quasi-aggregate were exposed on the surface and were not regularly oriented, as opposed to those in amyloid fibril. X-ray diffraction analysis indicated that the expansion of glutamine repeat did not show substantial effects on the β-sheet structure of pQ in fibril. Since the expansion of glutanine repeat in certain proteins is responsible for pQ diseases, the present study suggests that the condensed and non-oriented β-sheets exposed on the surface of quasi-aggregate, rather than the regularly aligned β-sheets in fibrils, are closely involved in recruitment of various functional proteins into aggregates, leading to the cellular dysfunction that causes pQ diseases. Thus, the quasi-aggregate form also should be targeted to the therapeutic strategy for pQ diseases.
Base on those structural change, we searched for compounds to stabilize the molecule with expanded polyglutamine and found some effective compounds. Less

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (31 results)

All Other

All Publications (31 results)

  • [Publications] Lee.J-A.et al.: "Aggregate formation and the impairment of long-term synaptic facilitation by ectopic expression of mutant huntingtin in Aplysia neurons"J.Neurochem. (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Park, T-J. et al.: "Inhibition of ubiquitin ligase Siah-1A by disabled-1"Biochem.Biophys.Res.Commun.. 302. 671-678 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanaka, M. et al.: "The effects of aggregation-inducing motifs on amyloid formation of model proteins related to neurodegenerative diseases"Biochemistry. 41. 10277-10286 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Mitsui, K. et al.: "Purification of polyglutamine aggregates and indentification of elongation factro-1α and heat shock protein 84 as aggregate-interacting proteins"J.Nuerosci. 22. 9267-9277 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanaka, M. et al.: "Intra-and intermolecular β-pleated sheet formation in glutamine-repeat inserted myoglobin as a model for polyglutamine diseases"J.Biol.Chem.. 276. 45470-45475 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwata, A. et al.: "α-synuclein affects the MAP kinase pathway and accelerates cell death"J.Biol.Chem.. 276. 45320-45329 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Jana, N-R. et al.: "Altered proteasemal function due to the expression of polyglutamine-expanded truncated N-terminal hutingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release"Hum.Mol.Genet.. 10. 1040-1059 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwata, A. et al.: "α-synuclein forms a complex with transcription factor Elk-1"J.Neurochem.. 77. 239-252 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 岩田 淳 ほか: "α-シヌクレインによる神経細胞死・・・(2)"臨床神経科学. 21. 126-127 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 岩田 淳 ほか: "α-シヌクレインによる神経細胞死・・・(1)"臨床神経科学. 21. 6-7 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 貫名信行, 田中元雅: "ポリグルタミン含有蛋白の構造変化-マックス・ペルツ最後の挑戦-"神経研究の進歩. 46. 661-668 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 貫名信行: "Huntington病"最新医学. 56. 1606-1610 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Lee. J-A., Lim, C-S., Lee, S-H., Kim, H., Nukina, N., Kaang, B-K.: "Aggregate formation and the impairment of long-term synaptic facilitation by ectopic expression of mutant huntingtin in Aplysia neurons"J. Neurochem.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Park, T-J., Hamanaka, H., Ohshima, T., Watanabe, N., Mikoshiba, K., Nukina, N.: "Inhibition of ubiquitin ligase Siah-IA by disabled-1"Biochem. Biophys. Res. Commun.. 302. 671-678 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanaka, M., Machida, Y., Nishikawa, Y., Akagi, T., Morishima, I., Hashikawa, T., Fujisawa, T., Nukina, N.: "The effects of aggregation-indueing motifs on amyloid formation of model proteins related to neurodegenerative diseases"Biochemistry. 41. 10277-10286 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Mitsui, K., Nakayama, H., Akagi, T., Nekooki, M., Ohtawa, K., Takio, K., Hashikawa, T., Nukina, N.: "Purification of polyglutamine aggregates and identification of elongation factor-1α and heat shock protein 84 as aggregate-interacting proteins"J. Neurosci.. 22. 9267-9277 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanaka, M., Morishima, I., Akagi, T., Hashikawa, T., Nukina, N.: "Intra- and intermolecular β-pleated sheet formation in glutamine-repeat inserted myoglobin as a model for polygulutamine diseases"J. Biol. Chem.. 276. 45470-45475 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwata, A., Maruyama, M., Kanazawa, I., Nukina, N.: "α-synuclein affects the MAP kinase pathway and accelerates cell death"J. Biol. Chem.. 276. 45320-45329 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Jana, N-R., Zemskov, E-A, Wang, G-H., Nukina, N.: "Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release"Hum. Mol. Genet.. 10. 1049-1059 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwata, A., Miura, S., Kanazawa, I., Sawada, M., Nukina, N.: "α-synuclein forms a complex with transcription factor Elk-1"J. Neurochem.. 77. 239-252 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Lee.J-A., et al.: "Aggregate formation and the impairment of long-term synaptic facilitation by ectopic expression of mutant huntingtin in Aplysia neurons"J.Neurochem.. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanaka, M., et al.: "The effects of aggregation-inducing motifs on amyloid formation of model proteins related to neurodegenerative diseases"Biochemistry. 41. 10277-10286 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Mitsui, K., et al.: "Purification of polyglutamine aggregates and identification of elongation factor-1α and heat shock protein 84 as aggregate-interacting proteins"J.Neurosci.. 22. 9267-9277 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 岩田 淳, 丸山美枝子, 貫名信行: "α-シヌクレインによる神経細胞死…(1)"臨床神経科学. 21. 6-7 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 貫名信行, 田中元雅: "ポリグルタミン含有蛋白の構造変化-マックス・ペルツ最後の挑戦-"神経研究の進歩. 46. 661-668 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Iwata, A. et al.: "α-synuclein forms a complex with transcription factor Elk-1"J. Neurochem.. 77. 239-252 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Jana, N-R. et al.: "Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release"Hum. Mol. Genet.. 10. 1049-1059 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Iwata, A. et al.: "α-synuclein effects the MAP kinase pathway and accelerates cell death"J. Biol. Chem.. 276. 45320-45329 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanaka, M. et al.: "Intra-and intermolecular β-pleated sheet formation in glutamine-repeat inserted myoglobin as a model for polygulutamine diseases"J. Biol. Chem.. 276. 45470-45475 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 貫名信行: "精神神経疾患のDNAチップ解析一緒についたDNAチップ解析"医学のあゆみ. 10. 785-788 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 貫名信行: "Huntington病"最新医学. 56. 1606-1610 (2001)

    • Related Report
      2001 Annual Research Report

URL: 

Published: 2001-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi