Molecular Mechanisms of Dopaminergic Neuronal Protection by Regulation of Proteasome Activity
| Project/Area Number |
16590823
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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 | Utano National Hospital, Clinical Research Center (2005)
Kyoto University (2004) |
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Principal Investigator |
SAWADA Hideyuki Utano National Hospital, Clinical Research Center, 臨床研究部, 臨床研究部長 (30335260)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMOHAMA Shun Kyoto University, Graduate School of Medicine, Assoiate Professor, 医学研究科, 助教授 (60235687)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Parkinson disease / Lewy body / proteasome / heat shock protein / dopamine / neuronal death / neurodegenerative disease / catecholamine / グルタチオン / 細胞死 / 封入体 / タンパク凝集 / 神経細胞死 / α-シヌクレイン |
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| Research Abstract |
Neurodegenerative disorders including Parkinson disease have common features, selective neuronal death and accumulation of insoluble proteins in the neurons. In Parkinson disease these two features are selective dopaminergic neuronal death and the appearance of alpha-synuclein positive Lewy bodies. In the previous research of Grant-in-Aid for Scientific Research (14570591), we reported that proteasome inhibition causes alpha-synuclein-positive inclusions, and on the contrary, it blocks dopaminergic neuronal death (Sawada et al., J.Biol.Chem.279:10710,2004). In this research we investigated the effect of proteasome inhibition on dopaminergic neuronal degeneration in vivo using animal hemi-Parkinson model by 6-hydroxy dopamine (6-OHDA). Histological analysis revealed that proteasome inhibition blocks dopaminergic neuronal degeneration in this model, and behavioral analysis showed that hemi-Parkinsonism is blocked by proteasome inhibition (Inden et al., J.Pharmacol.Sci.97:203-211,2005). These results seem paradoxical because previous hypothesis suggest that accumulation of insoluble proteins could cause dopaminergic neuronal degeneration.
In this research we investigated the molecular mechanisms of neuroprotection by proteasome inhibition and found that proteasome inhibition elevated heat shock protein 70 (HSP7O) and glutathione (submitted and revised). In addition we reported that dopaminergic neuronal death by 6-OHDA is mediated by p-quinone, toxic dopamine intermediates (Izumi et al. J.Neurosci.Res. 79:849,2005;Izumi et al., J.Neurosci.Res.82:126-137,2005). Furthermore, we reported that sympathetic norepinephrine neuronal terminals in the papillary sphincter muscles are disturbed in patients in the disease (Sawada et al., JAMA 293:932-924,2005).
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Report
(3 results)
Research Products
(30 results)
