2002 Fiscal Year Final Research Report Summary
Effects of molecular chaperones on polyQ-mediated cell death and toxicity using cellular model of SBMA
| Project/Area Number |
13670674
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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 | Kyoto Pharmaceutical University |
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Principal Investigator |
HATAYAMA Takumi Kyoto Pharmaceutical University, Professor, 薬学部, 教授 (10094484)
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| Co-Investigator(Kenkyū-buntansha) |
OHTSUKA Kenzo Chubu University, Professor, 応用生物学部, 教授 (40150213)
ISHIHARA Keiichi Kyoto Pharmaceutical University, Research Associate, 薬学部, 助手 (80340446)
YAMAGISHI Nobuyuki Kyoto Pharmaceutical University, Lecturer, 薬学部, 講師 (60298685)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Molecular chaperone / Polygultamine disease / Hsp105 / Hsp70 / Hsp40 / Apoptosis / SBMA |
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| Research Abstract |
1. We examined the effects of Hsp105α on the aggregate formation and cytotoxicity caused by expansion of polyQ tracts using cellular model of SBMA. The transient expression of truncated androgen receptors (tARs) containing expanded polyQ tracts induced aggregate formation in COS-7 and SK-N-SH cells and concomitantly apoptotic cell death in these cells with nuclear aggregates. When Hsp105α was over-expressed with tAR97 in cells, the aggregate formation and cytotoxicity caused by expansion of polyQ tracts were markedly reduced. Both β-sheet and α-helix domains, but not ATPase domain, of Hsp105α were necessary for the suppression of the aggregate formation in vivo and in vitro. Furthermore, Hsp105α was found to localize in nuclear inclusions formed by Ars containing expanded polyQ tracts in tissues of patients and transgenic mice with SBMA. These findings suggest that over-expression of Hsp105α suppresses cell death caused by expansion of polyQ tracts without chaperone activity, and the enhanced expression of the essential domains of Hsp105α in brain may provide an effective therapeutic mean for CAG repeat diseases.
2. We examined the effect of carrier protein on the aggregate formation and cytotoxicity caused by expansion of polyQ tracts. When truncated Ars containing expanded polyQ tracts fused to GFP (tAR24 and tAR97) or expanded polyQ tracts fused to GFP (polyQ24 and polyQ97) were expressed in COS-7 cells, polyQ97 caused marked aggregate formation and apoptosis than tAR97 did. Furthermore, although both tAR24 and polyQ24 did not cause their aggregation, polyQ24 but not tAR24 induced apoptosis. Thus, it was suggested that protein carrying polyQ tracts affects the cytotoxicity of polyQ tract.
3. Proteome analysis is now progress to find proteins which are responsible for cytotoxicity and apoptosis of cells expressing tARs containing expanded polyQ tracts.
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Research Products
(19 results)
