Molecular mechanism of degeneration of dopaminergic neurons caused by 8-oxoguanine

2016 Fiscal Year Final Research Report

• Project/Area Number: 26460490
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Kyushu University
• Principal Investigator: Sheng Zijing 九州大学, 生体防御医学研究所, 特別研究員 (90467895)
• Co-Investigator(Renkei-kenkyūsha): Nakabeppu Yusaku 九州大学, 生体防御医学研究所, 教授 (30180350)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 8-oxoG / パーキンソン病 / MTH1 / OGG1 / MUTYH

Outline of Final Research Achievements

We investigated roles of MTH1, OGG1, and MUTYH in the molecular pathological mechanisms by which oxidative stress induces degeneration of dopaminergic neurons. Ogg1/Mth1-DKO mice administered MPTP, a dopaminergic neurotoxin, which is known to cause Parkinsonism, displayed hyperactivity, namely hyperkinesis, in open field test compared to wild-type mice. The Ogg1/Mth1-DKO mice also showed a more pronounced reduction in grip strength compared to the wild-type mice. Furthermore, it was revealed that human MTH1 transgenic mice overexpressing hMTH1 showed remarkable resistance to the hyperkinesis induced by MPTP. Ogg1-KO mice as well as wild-type mice exhibited hyperkinesia after MPTP administration, however Ogg1/Mutyh-DKO mice showed no hyperkinesis induced by MPTP. These data suggest that MTH1 and OGG1 may protect nigrostriatal dopaminergic neurons, while base excision repair initiated by MUTYH may trigger degeneration of the dopaminergic neurons.

Free Research Field

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