Function of DJ-1, a causative gene for familial Parkinson's disease PARK7
| Project/Area Number |
16390248
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | HOKKAIDO UNIVERSITY |
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Principal Investigator |
ARIGA Sanae Hokkaido Univ., Grad.School of Agr., Professor, 大学院・農学研究科, 教授 (90184283)
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| Co-Investigator(Kenkyū-buntansha) |
ARIGA Hiroyoshi Hokkaido Univ., Grad.School of Pharma.Sci., Professor, 大学院・薬学研究科, 教授 (20143505)
TAIRA Takahiro Yamanashi Univ., Grad.School of Med., Professor, 大学院・医学総合研究部, 教授 (70197036)
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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 |
¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2005: ¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 2004: ¥7,400,000 (Direct Cost: ¥7,400,000)
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| Keywords | Neuroscience / Genomics / proteome / neurodegenerative disease / genome / DJ-1 / パーキンソン病 / 酸化ストレス / 神細細胞死 / ミトコンドリア / SUMO-1 / プロテアーゼ / 転写調節 |
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| Research Abstract |
DJ-1 has recently been shown to be responsible for onset of familial Parkinson's disease (PD), PARK7. We have shown that DJ-1 plays roles in transcriptional regulation and anti-oxidative stress, and loss of its function is thought to trigger onset of PD. We and others have also shown that some DJ-1 is located in mitochondria in addition to the cytoplasm and nucleus and that translocation of DJ-1 to mitochondria was stimulated by oxidative stress. Furthermore, we found that DJ-1 was a positive regulator of the mitochondrial complex 1 by binding to its subunit.
When a recombinant DJ-1 protein was administrated into the brain of PD model rats that had been injected to 6-hydroxydopamine (6-OHDA) in the left substantia nigra, PD phenotypes, including dopaminergic neuron death both in the substantia nigra and striatum, decrease in dopamine and dopamine transporter levels in the striatum, and motor abnormality, were dramatically improved by wild-type DJ-1 but not L166P DJ-1, a mutant form of DJ-1 found in PD patients. Furthermore, production of reactive oxygen species and cell death induced by 6-OHDA in SH-SY5Y cells were inhibited by addition of the recombinant DJ-1. We then screened low-molecular weight compounds that bind to the catalytic region of DJ-1 and found that these compounds protected SH-SY5Y cells from oxidative stress-induced cell death by inhibiting oxidation of DJ-1.
These findings suggest that DJ-1 and its binding compounds are therapeutic targets for PD.
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Report
(3 results)
Research Products
(33 results)
