2003 Fiscal Year Final Research Report Summary
Proteasome regulates dopaminergic neuronel degeneration and Lewy body formation
| Project/Area Number |
14570591
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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 UNIVERSITY |
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Principal Investigator |
SAWADA Hideyuki KYOTO UNIVERSITY, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (30335260)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMOHAMA Shun KYOTO UNIVERSITY, Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (60235687)
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| Project Period (FY) |
2002 – 2003
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| Keywords | Parkinson's disease / α-synuclein / MPP^+ / rotenone / proteasome / Lewy body / dopamine |
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| Research Abstract |
Parkinson's disease is characterized by dopaminergic neuronal death and the presence of Lewy bodies. α-Synuclein is a major component of Lewy bodies, but the process of its accumulation and its relationship to dopaminergic neuronal death have not been resolved. Although the pathogenesis has not been clarified, mitochondrial complex I is suppressed and caspase-3 is activated in the affected midbrain. In this research project, we demonstrated that a combination of 1-methyl-4-phenylpyridinium ion (MPP^+) or rotenone and proteasome inhibition caused the appearance of α-synuclein positive inclusion bodies. Unexpectedly, however, proteasome inhibition blocked MPP^+-or rotenone-induced dopaminergic neuronal death. MPP^+ elevated the activity of 26S proteasome, dephosphorylated mitogen activating kinase (MAPK) and activated caspase-3. Proteasome inhibition reversed the MAPK dephosphorylation and blocked caspase-3 activation; the neuroprotection was blocked by a p-42 and p-44 MAPK kinase inhibitor. Thus the proteasome plays an important role in both inclusion body formation and dopaminergic neuronal death but these processes form opposite sides on the proteasome regulation in this model.
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Research Products
(20 results)
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[Publications] Nakamizo T, Kawamata J, Yoshida K, Kawai Y, Kanki R, Sawada H, Kihara T, Yamashita H, Shibasaki H, Akaike A, Shimohama S.: "Phosphodiesterase inhibitors are neuroprotective to cultured spinal motor neurons."J.Neurosci Res.. 71. 485-495 (2003)
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「研究成果報告書概要(欧文)」より
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[Publications] Sawada H, Kohno R, Kihara T, Izumi Y, Sakka N, Ibi M, Nakanishi M, Nakamizo T, Yamakawa K, Shibasaki H, Yamamoto N, Akaike A, Inden M, Kitamura Y, Taniguchi T, Shimohama S.: "Proteasome mediates dopaminergic neuronal deaeneration, and its inhibition causes alpha-"J.Biol.Chem.. 279. 10710-10719 (2004)
Description
「研究成果報告書概要(欧文)」より
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