IDENTIFICATION AND CHARACTERIZATION OF A NOVEL UBIQUITIN LIGASE SIAH THAT EXHIBITS COMPLEMENTARY ROLES WITH PARKIN
| Project/Area Number |
15590893
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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 | HIROSHIMA UNIVERSITY |
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Principal Investigator |
YAMASHITA Hiroshi Hiroshima University, Graduate School of Biomedical Sciences, Assistant Professor, 大学院・医歯薬学総合研究科, 助手 (20311813)
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| Co-Investigator(Kenkyū-buntansha) |
HATTORI Nobutaka Juntendo University, School of Medicine, Associate Professor, 医学部, 助教授 (80218510)
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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: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | Parkinson's disease / Parkin / α-synuclein / SIAH / Synphilin-1 / ubiquitination / ubiquitin lipase / Lewy body / α-Synuclein / Synphilin-1 / Siah-1 / ユビキチン / ドーパミン |
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| Research Abstract |
Parkinson's disease is a common neurodegenerative disorder characterized by loss of dopaminergic neurons and appearance of Lewy bodies, cytoplasmic inclusions that are highly enriched with ubiquitin. Synphilin-1, α-synuclein and Parkin represent the major components of Lewy bodies, and are involved in pathogenesis of Parkinson's disease. Synphilin-1 is anα-synuclein binding protein that is ubiquitinated by Parkin. Recently, a mutation in the synphilin-1 gene is reported in patients with sporadic Parkinson's disease. Although synphilin-1 localizes close to synaptic vesicles, its function remains unknown. To investigate the proteins that interact with synphilin-1, the present study performed a yeast two-hybrid screening and identified a novel interacting protein, Siah-1 ubiquitin ligase. Synphilin-1 and Siah-1 proteins were endogenously expressed in the central nervous system, and coimmunoprecipitated each other in rat brain homogenate. Confocal microscopic analysis revealed colocalization of both proteins in cells. Siah-1 was found to interact with the N-terminus of synphilin-1 through its substrate-binding domain, and specifically ubiquitinate synphilin-1 via its RING finger domain. Siah-1 facilitated synphilin-1 degradation via the ubiquitin-proteasome pathway more efficiently than Parkin. Siah-1 was found not to facilitate ubiquitination and degradation of wild type or mutant α-synuclein. Synphilin-1 inhibited high K^+-induced dopamine release from PC12 cells. Siah-1 was found to abrogate the inhibitory effect of synphilin-1 on dopamine release. Such findings suggest that Siah-1 might play a role in regulation of synphilin-1 function.
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Report
(3 results)
Research Products
(8 results)
