Neuronal NOS and cyclooxygenase-2 contribute to DNA damage in a mouse model of Parkinson disease
Neuronal NOS and cyclooxygenase-2 contribute to DNA damage in a mouse model of Parkinson disease
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DOI：
10.1016/j.freeradbiomed.2009.07.013
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发表时间：
2009-10-01
影响因子：
7.4
通讯作者：
Przedborski, Serge
中科院分区：
文献类型：
--
作者：
Hoang, Tuan;Choi, Dong-Kug;Przedborski, Serge
DNA损伤是神经退行性疾病如帕金森病的一种致病因素。为了探索这种神经元扰动的基础机制，我们试图建立一个DNA损伤的实验模型。因此，我们首先通过原位切口平移和乳剂放射自显影术评估了小鼠脑中给予1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP; 4x 20 mg/kg，ip，每2 h一次）后的DNA损伤，MPTP是一种已知可产生帕金森病模型的神经毒素。在这里，我们表明，DNA链断裂发生在体内的动力学和地形学，平行的黑质神经元的变性，如FluoroJade标记的帕金森病的小鼠模型。以前，一氧化氮合酶和环氧合酶-2（考克斯-2）被发现调节MPTP诱导的多巴胺能神经元死亡。因此，我们评估了这些酶对缺乏神经元型一氧化氮合酶（nNOS）、诱导型一氧化氮合酶（iNOS）或考克斯-2的小鼠DNA损伤的贡献。我们发现，缺乏考克斯-2和nNOS活性，但没有iNOS活性减弱MPTP相关的DNA损伤。我们还发现，不仅细胞核，而且线粒体，DNA是MPTP损伤的目标。这些结果表明，基因组完整性的丧失可以触发的nNOS和考克斯-2的协同作用，并提供进一步的支持，认为DNA损伤可能有助于帕金森病的神经退行性过程。(C)2009 Elsevier Inc. All rights reserved.
DNA damage is a proposed pathogenic factor in neurodegenerative disorders such as Parkinson disease. To probe the underpinning mechanism of such neuronal perturbation, we sought to produce an experimental model of DNA damage. We thus first assessed DNA damage by in situ nick translation and emulsion autoradiography in the mouse brain after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 4x20 mg/kg, ip, every 2 h), a neurotoxin known to produce a model of Parkinson disease. Here we show that DNA strand breaks occur in vivo in this mouse model of Parkinson disease with kinetics and a topography that parallel the degeneration of substantia nigra neurons, as assessed by FluoroJade labeling. Previously, nitric oxide synthase and cyclooxygenase-2 (Cox-2) were found to modulate MPTP-induced dopaminergic neuronal death. We thus assessed the contribution of these enzymes to DNA damage in mice lacking neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), or Cox-2. We found that the lack of Cox-2 and nNOS activities but not of iNOS activity attenuated MPTP-related DNA damage. We also found that not only nuclear, but also mitochondrial, DNA is a target for the MPTP insult. These results suggest that the loss of genomic integrity can be triggered by the concerted actions of nNOS and Cox-2 and provide further support to the view that DNA damage may contribute to the neurodegenerative process in Parkinson disease. (C) 2009 Elsevier Inc. All rights reserved.