| Project/Area Number |
17590887
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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 | Kagoshima University |
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Principal Investigator |
TAKASHIMA Hiroshi Kagoshima University, Graduate School of Medical and Dental Sciences, Research Associate, 大学院医歯学総合研究科, 助手 (80372803)
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| Co-Investigator(Kenkyū-buntansha) |
ARIMURA Kimiyoshi Kagoshima University, Graduate School of Medical and Dental Sciences, Associate professor, 大学院医歯学総合研究科, 助教授 (20159510)
MATSUYAMA Wataru Kagoshima University, Graduate School of Medical and Dental Sciences, Research Associate, 大学院医歯学総合研究科, 助手 (90372804)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | spinocerebellar degeneration / inherited neuropathy / DNA repair / SCAN1 / TDP1 |
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| Research Abstract |
We reported the recessive His493Arg mutation of Tyrosyl-DNA phosphodiesterase 1 (Tdp1) has been associated with neurodegeneration through segregation of a TDP1 mutation with spinocerebellar ataxia with axonal neuropathy (SCAN1). Tdp1 is a component of DNA single stranded and double stranded damage repair repairing several types of DNA damage including topoisomerase I-DNA complexes. Clarifying the biology of Tdp1 in the nervous system is critical for understanding the role of Tdp1 and Topoisomerase I (TopoI) in predisposing to neurodegeneration. Based on our expression studies of candidate DNA repair genes, the Ercc1/Xpf pathway could function redundant to Tdp1 in neuronal DNA repair. The Tdp1 mice that we generated did not exhibit behavioral or histopathological changes, peripheral nerve electrophysiological abnormalities throughout 16 weeks. On the other hand, by intraperitoneal administration of the Topo1 inhibitor CPT-11 to Tdp1(knockout) and Tdp1(knockout) mice, we showed that although CPT-11 had no effect on the Tdp1(Wild) mice, the Tdp1 (knockout) mice showed motor disturbance and lethality. We proofed some relationship between the loss of Tdp1 activity and neuronal degeneration.
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