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IN VITRO CELLULAR MODEL FOR MACHADO-JOSEPH DESEASE, A MODEL FOR TRIPLET REPEAT DISEASES.

Research Project

Project/Area Number 10670572
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionUniversity of Tsukuba

Principal Investigator

YOSHIZAWA Toshihiro  ASSISTANT PROFESSOR DEPARTMENT OF NEUROLOGY, INSTITUTE OF CLINICAL MEDICINE, UNIVERSITY OF TSUKUBA, 臨床医学系, 講師 (50212311)

Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1998: ¥1,600,000 (Direct Cost: ¥1,600,000)
KeywordsMachado-Joseph disease / polyglutamine / ataxin-3 / cell death / cell cycle / aggregation / neuron / マシャド・ジョセフ病 / ポリグルタシ鎖
Research Abstract

Machado-Joseph disease (MJD) is an inherited neurodegenerative disorder caused by the expansion of the polyglutamine stretch in the MJD-gene coding protein (ataxin-3). Using a series of deletion constructs expressing ataxin-3 fragments with the expanded polyglutamine stretch, we observed aggregate formation and cell death in the cultured BHK-21 cells. The cytotoxic effect of the N-terminal-truncated ataxin-3 with the expanded polyglutamine tract was enhanced under the serum-starved culture condition, in which the cells were arrested in the G0/G1 phase. Co-expression of p21ィイD1waf1/cip1/sdi1ィエD1, a cyclin-Cdk inhibitor, that induced cell cycle arrest in the G1 phase, also increased the susceptibility to cell death produced by the mutant ataxin-3 fragment in BHK-21 cells. Finally, the elevated susceptibility to cell death in the G0/G1 phase was confirmed in the nerve growth factor-treated, postmitotic neuronal PC12 cells compared to the undifferentiated proliferating PC12 cells. These results strongly suggest that the cellular toxicity of the truncated ataxin-3 with the expanded polyglutamine stretch is enhanced by cell cycle arrest in the G0/G1 phase. The mutant ataxin-3 may confer a higher susceptibility to cell death on the cells in the G0/G1 phase.

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (7 results)

All Other

All Publications (7 results)

  • [Publications] T.Yoshizawa: "Cell cycle arrest enhanced the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch"Human Molecular Genetics. Vol.9, No.1. 69-78 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 吉澤 利弘: "Machado-Joseph病"クリニカルニューロサイエンス. Vol.18, No.4 (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yoshizawa T, Yamagishi Y, Koseki N, Goto J, Yoshida H, Shibasaki F, Shoji S, Kanazawa I: "Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch."Hum. Mol. Genet.. 9. 69-78 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T.Yoshizawa: "Cell cycle arrest enhanced the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch."Human Molecular Genetics. Vol 9,NO. 1. 69-78 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 吉澤 利弘: "「Machado-Joseph 病」"クリニカルニューロサイエンス. Vol 18,NO. 4 (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 白岩伸子 ほか: "Balo病様のMRI所見を臨床経過と比較し得た急性白質脳症の2例" 神経内科. 49. 59-66 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yoshizawa T et al.: "L-threo-3,4-dihydroxyphenylsemine enhances the orthostatic responses of plasma renin activity and angiotersinll in multipk system atreply" J.of Neurology. (in press).

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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