NADPH Oxidase 1-Mediated Oxidative Stress Leads to Dopamine Neuron Death in Parkinson's Disease
NADPH Oxidase 1-Mediated Oxidative Stress Leads to Dopamine Neuron Death in Parkinson's Disease
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DOI：
10.1089/ars.2011.3960
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发表时间：
2012-05-01
影响因子：
6.6
通讯作者：
Kim, Yoon-Seong
中科院分区：
文献类型：
--
作者：
Choi, Dong-Hee;Cristovao, Ana Clara;Kim, Yoon-Seong
目的：氧化应激一直被认为是帕金森病发病机制中的一个主要因素。然而，帕金森氏病中活性氧的分子来源尚未明确阐明。在此，我们试图调查是否超氧化物产生NADPH氧化酶（NOX）参与氧化应激介导的多巴胺能神经元变性。结果：在N27，大鼠多巴胺能细胞的各种Nox亚型和胞质成分的表达进行了研究。虽然大多数的Nox亚型组成型表达，Nox1的表达显着增加治疗后与6-羟基多巴胺。Nox 1系统中的关键调节因子Rac 1也被激活。纹状体注射6-羟基多巴胺增加大鼠黑质多巴胺能神经元Nox 1的表达。有趣的是，它被定位到细胞核中，并且DNA氧化应激标记物8-oxo-dG的免疫染色增加。在帕金森病患者黑质多巴胺能神经元核中也发现了Nox 1的表达。腺相关病毒介导的Nox 1敲除或Rac 1抑制可显著降低6-羟基多巴胺诱导的DNA氧化损伤和多巴胺能神经元变性。创新：Nox1/Rac1可以作为帕金森病的潜在治疗靶点。结论：多巴胺能神经元具有Nox 1/Rac 1超氧化物生成系统。应激诱导的Nox1/Rac1活化导致氧化性DNA损伤和神经退行性变。通过靶向Nox1/Rac1实现的减少多巴胺能神经元死亡强调了由该系统引起的氧化应激对帕金森病发病机制和治疗的影响。抗氧化剂。氧化还原信号。16，1033 - 1045。
Aim: Oxidative stress has long been considered as a major contributing factor in the pathogenesis of Parkinson's disease. However, molecular sources for reactive oxygen species in Parkinson's disease have not been clearly elucidated. Herein, we sought to investigate whether a superoxide-producing NADPH oxidases (NOXs) are implicated in oxidative stress-mediated dopaminergic neuronal degeneration. Results: Expression of various Nox isoforms and cytoplasmic components were investigated in N27, rat dopaminergic cells. While most of Nox isoforms were constitutively expressed, Nox1 expression was significantly increased after treatment with 6-hydroxydopamine. Rac1, a key regulator in the Nox1 system, was also activated. Striatal injection of 6-hydroxydopamine increased Nox1 expression in dopaminergic neurons in the rat substantia nigra. Interestingly, it was localized into the nucleus, and immunostaining for DNA oxidative stress marker, 8-oxo-dG, was increased. Nox1expression was also found in the nucleus of dopaminergic neurons in the substantia nigra of Parkinson's disease patients. Adeno-associated virus-mediated Nox1 knockdown or Rac1 inhibition reduced 6-hydroxydopamine-induced oxidative DNA damage and dopaminergic neuronal degeneration significantly. Innovation: Nox1/Rac1 could serve as a potential therapeutic target for Parkinson's disease. Conclusion: We provide evidence that dopaminergic neurons are equipped with the Nox1/Rac1 superoxide-generating system. Stress-induced Nox1/Rac1 activation causes oxidative DNA damage and neurodegeneration. Reduced dopaminergic neuronal death achieved by targeting Nox1/Rac1, emphasizes the impact of oxidative stress caused by this system on the pathogenesis and therapy in Parkinson's disease. Antioxid. Redox Signal. 16, 1033-1045.