Studies of polyQ diseases : possible mechanisms of cell death and its prevention by molecular chaperone
| Project/Area Number |
15590915
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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, Department of Biochemistry, Professor, 薬学部, 教授 (10094484)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAGISHI Nobuyuki Kyoto pharmaceutical University, Department of Biochemistry, Lecturer, 薬学部, 講師 (60298685)
ISHIHARA Keiichi Kyoto pharmaceutical University, Department of Biochemistry, Research associate, 薬学部, 助手 (80340446)
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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 |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Polygultamine disease / SBMA / Molecular chaperone / Apoptosis / NSAIDs / Hsp105 / Hsp70 |
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| Research Abstract |
We analyzed the apoptotic pathway induced by proteins containing expanded polyQ tract (97 or 24) using cellular model of Spinal and bulbar muscular atrophy (SBMA). When expression plasmids of truncated ARs containing polyQ tracts fused to GFP (tAR24 and tAR97) or polyQ tracts fused to GFP (polyQ24 and polyQ97) were transfected into COS-7 cells, tAR97 and polyQ97, but not tAR24 and polyQ24, induced marked formation of the aggregates and apoptosis in the cells with nuclear aggregates.
To examine the apoptotic pathway induced by the polyQ proteins, we next esatablished HeLa-tet cell lines in which expression of PolyQ proteins was regulated by doxycycline. In apoptotic cells, the transition of Bax to mitochondria, release of cytochrome c and activation of caspase 3 were observed concomitantly with the expression of polyQ97. However, unfolded protein response was not observed in these cells. Thus, polyQ97-induced apoptosis seemed to be in part occurred through the mitochondrial pathway via Bax.
As the over-expression of heat shock proteins (hsp) suppresses cell death caused by expansion of the polyQ tract, the enhanced expression of hsp may provide an effective therapeutic approach for polyQ diseases. We found that non-steroid anti-inflamatory drugs such as sodium salicylate and indomethacin up-regulated the hsp promoter at 37℃ through the activation of heat shock factor and induced the increased accumulation of hsp in mammalian cells, and also revealed that sodium salicylate and indomethacin suppressed the aggregation of polyQ97 and apoptosis caused by an expanded polyQ tract. Thus, NSAIDs seemed to be used for the protection of cells against deleterious stressors and neurodegenerative diseases.
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Report
(3 results)
Research Products
(16 results)
