Evaluation of suppressive effects of drugs on cell death using cellular and transgenic models of polyglulamine disease.
| Project/Area Number |
15590877
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | University of Tsukuba |
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Principal Investigator |
YOSHIZAWA Toshihiro University of Tsukuba, Graduate School of Comprehensive Human Science, Assistant Professor, 大学院・人間総合科学研究科, 講師 (50212311)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | polyglutamine disease / Machado-Joseph Disease / ectoine / cell death / aggregation / ataxin-3 / マシャド・ジョセア病 |
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| Research Abstract |
Protein misfolding is considered a key event in the pathogenesis of polyglutamine disease such as Machado-Joseph disease(MJD). Overexpression of chaperone proteins and the application of chemical chaperones are reported to suppress polyglutamine induced cytotoxicity in vitro and in vivo. The effects of compatible solutes, which are osmoprotectants in bacteria and possess the action in stabilizing proteins under stress, have not, to our knowledge, been studied. We explored the protective effects of the compatible solutes ectoine, on apoptotic cell death produced by the truncated MJD gene product with an expanded polyglutamine tract in cultured neuro2a cells. Ectoine decreased large cytoplasmic inclusions and increased the frequency of nuclear inclusions. The total amount of aggregates was reduced by ectoine on the immunoblot analysis. Despite the presence of nuclear inclusions, apoptotic features were less observed after the application of ectoine. Our findings suggest that the natural osmoprotectant in bacteria, ectoine, may function as a novel type of molecules which protect cells from polyglutamine-induced toxicity.
Next, using orexin-ataxin transgenic mice, which express the truncated MJD gene product with an expanded polyglutamine tract under the control of orexin promoter and demonstrate cell death of orexin neurons in hypothalamus, we examined the effects of ectoine in vivo. Intraperitoneally administered ectoine (50〜100 mg/kg body weight) seemed to attenuate the decrease of orexin neurons based on the immunohistochemical analyses of brains. However, further confirmation will be necessary.
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Report
(3 results)
Research Products
(8 results)
