NADPH oxidase 1 mediates α-synucleinopathy in Parkinson's disease.
NADPH oxidase 1 mediates α-synucleinopathy in Parkinson's disease.
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DOI：
10.1523/jneurosci.2246-12.2012
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发表时间：
2012-10-17
期刊：
影响因子：
--
通讯作者：
Kim YS
中科院分区：
文献类型：
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作者：
Cristóvão AC;Guhathakurta S;Bok E;Je G;Yoo SD;Choi DH;Kim YS
错误折叠的α-突触核蛋白的积聚是帕金森病（PD）的病理标志。然而，对α-突触核蛋白聚集的机制及其对多巴胺能神经元的进一步毒性知之甚少。由于氧化应激可增加α-突触核蛋白的表达和聚集水平，负责ROS产生的NADPH氧化酶（NOX）可能是α-突触核蛋白病的主要参与者。以前，我们证明了Nox 1在PD动物模型的多巴胺能神经元以及PD患者的死后脑组织中表达，负责氧化应激和随后的神经元变性。在这里，使用百草枯（PQ）为基础的体外和体内PD模型，我们表明，Nox 1在调节多巴胺能神经元中的α-突触核蛋白表达和聚集的行为中具有至关重要的作用。我们在分化的人多巴胺能细胞中观察到，PQ暴露下Nox 1和α-突触核蛋白表达增加。Nox 1敲低显著降低α-突触核蛋白的表达和聚集，支持Nox 1在此过程中的作用。此外，在暴露于PQ的大鼠中，使用编码Nox 1特异性shRNA的腺相关病毒选择性敲低黑质中的Nox 1，大大减弱了PQ介导的α-突触核蛋白和泛素表达水平以及α-突触核蛋白聚集体（蛋白酶K抗性）和A11寡聚体的增加。还观察到氧化应激水平和多巴胺能神经元损失显著降低。我们的数据揭示了α-突触核蛋白通过Nox 1介导的氧化应激成为神经病理蛋白的新机制。这一发现可用于产生新的治疗干预措施，减缓α-突触核蛋白聚集的速率和PD发病机制的进展。
Accumulation of misfolded α-synuclein is the pathological hallmark of Parkinson’s disease (PD). Nevertheless, little is known about the mechanism contributing to α-synuclein aggregation and its further toxicity to dopaminergic neurons. Since oxidative stress can increase the expression and aggregation levels of α-synuclein, NADPH oxidases (NOXs), which are responsible for ROS generation, could be major players in α-synucleinopathy. Previously, we demonstrated that Nox1 is expressed in dopaminergic neurons of the PD animal models as well as postmortem brain tissue of PD patients, being responsible for oxidative stress and subsequent neuronal degeneration. Here, using paraquat (PQ)-based in vitro and in vivo PD models, we show that Nox1 has a crucial role in modulating the behavior of α-synuclein expression and aggregation in dopaminergic neurons. We observed in differentiated human dopaminergic cells that Nox1 and α-synuclein expression are increased under PQ exposure. Nox1 knockdown significantly reduced both α-synuclein expression and aggregation, supporting the role of Nox1 in this process. Furthermore, in rats exposed to PQ, the selective knockdown of Nox1 in the substantia nigra, using adeno-associated virus encoding Nox1-specific shRNA, largely attenuated the PQ-mediated increase of α-synuclein and ubiquitin expression levels as well as α-synuclein aggregates (proteinase-K resistant) and A11 oligomers. Significant reductions in oxidative stress level and dopaminergic neuronal loss were also observed. Our data reveal a new mechanism by which α-synuclein becomes a neuropathologic protein through Nox1-mediated oxidative stress. This finding may be used to generate new therapeutic interventions that slower the rate of α-synuclein aggregation and the progression of PD pathogenesis.