6-OHDA generated ROS induces DNA damage and p53- and PUMA-dependent cell death.
6-OHDA generated ROS induces DNA damage and p53- and PUMA-dependent cell death.
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DOI：
10.1186/1750-1326-6-2
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发表时间：
2011-01-06
影响因子：
15.1
通讯作者：
O'Malley KL
中科院分区：
文献类型：
--
作者：
Bernstein AI;Garrison SP;Zambetti GP;O'Malley KL
帕金森病（PD）的特征是黑质（SN）中多巴胺能神经元的选择性丧失，导致震颤、僵硬和运动迟缓。虽然病因尚不清楚，但多巴胺（DA）衍生物6-羟基多巴胺（6-OHDA）可以产生pd样症状，从而深入了解疾病过程。研究表明，6-OHDA激活应激通路，如未折叠蛋白反应（UPR），触发线粒体释放细胞色素c，激活caspase，如caspase-3。由于仅bh3蛋白Puma （p53上调的凋亡介质）在UPR下被激活，因此它被认为是细胞应激和凋亡之间的联系。为了验证Puma在6-OHDA介导的细胞死亡中起作用的假设，我们比较了野生型和无Puma小鼠多巴胺能神经元对6-OHDA的反应。结果表明，在原代分离的中脑培养物和体内，6-羟色胺诱导的细胞死亡需要Puma。在这些培养中，6-羟色胺诱导的DNA损伤和p53是6-羟色胺诱导的细胞死亡所必需的。相比之下，虽然6-OHDA导致UPR标记上调，但ATF3的缺失对6-OHDA没有保护作用。总之，我们的研究结果表明，6-羟色胺诱导的Puma上调和细胞死亡是独立于UPR的。相反，p53和DNA损伤修复途径介导6-羟多巴胺诱导的毒性。
Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN), resulting in tremor, rigidity, and bradykinesia. Although the etiology is unknown, insight into the disease process comes from the dopamine (DA) derivative, 6-hydroxydopamine (6-OHDA), which produces PD-like symptoms. Studies show that 6-OHDA activates stress pathways, such as the unfolded protein response (UPR), triggers mitochondrial release of cytochrome-c, and activates caspases, such as caspase-3. Because the BH3-only protein, Puma (p53-upregulated mediator of apoptosis), is activated in response to UPR, it is thought to be a link between cell stress and apoptosis. To test the hypothesis that Puma serves such a role in 6-OHDA-mediated cell death, we compared the response of dopaminergic neurons from wild-type and Puma-null mice to 6-OHDA. Results indicate that Puma is required for 6-OHDA-induced cell death, in primary dissociated midbrain cultures as well as in vivo. In these cultures, 6-OHDA-induced DNA damage and p53 were required for 6-OHDA-induced cell death. In contrast, while 6-OHDA led to upregulation of UPR markers, loss of ATF3 did not protect against 6-OHDA. Together, our results indicate that 6-OHDA-induced upregulation of Puma and cell death are independent of UPR. Instead, p53 and DNA damage repair pathways mediate 6-OHDA-induced toxicity.
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