Peroxiredoxin-2 protects against 6-hydroxydopamine-induced dopaminergic neurodegeneration via attenuation of the apoptosis signal-regulating kinase (ASK1) signaling cascade.
Peroxiredoxin-2 protects against 6-hydroxydopamine-induced dopaminergic neurodegeneration via attenuation of the apoptosis signal-regulating kinase (ASK1) signaling cascade.
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Peroxiredoxin-2 通过减弱凋亡信号调节激酶 (ASK1) 信号级联来防止 6-羟基多巴胺诱导的多巴胺能神经变性。
DOI：
10.1523/jneurosci.4589-10.2011
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发表时间：
2011-01-05
期刊：
影响因子：
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通讯作者：
Chen J
中科院分区：
文献类型：
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作者：
Hu X;Weng Z;Chu CT;Zhang L;Cao G;Gao Y;Signore A;Zhu J;Hastings T;Greenamyre JT;Chen J
过氧化氧还蛋白（PRX）家族抗氧化酶有助于维持细胞内还原环境并抑制非神经元细胞的凋亡。然而，PRX是否可以通过特定的信号机制抑制神经元凋亡仍不清楚。PRX2是最丰富的神经元PRX，在帕金森病（PD）患者的大脑中发生诱导，但其功能影响尚不清楚。本研究以多巴胺能（DA）毒素6-羟多巴胺（6-OHDA）为模型，探讨PRX对DA神经元的保护作用及其机制。在MN9D DA神经元中检测的2-半胱氨酸prx中，内源性PRX2最有利于细胞存活。慢病毒介导的PRX2过表达在体外和体内对DA神经元的6-OHDA毒性具有显著的神经保护作用，并保留了小鼠多巴胺系统的运动功能。除了作为抗氧化酶的作用外，PRX2还通过抑制ask1依赖性的JNK/c-Jun和p38促死亡通路的激活，在DA神经元中表现出抗凋亡作用，这些通路也在死后PD脑的DA神经元中被激活。PRX2通过调节内源性ASK1抑制剂硫氧还蛋白（Trx）的氧化还原状态，抑制6- ohda诱导的ASK1激活。PRX2过表达通过抑制半胱氨酸硫-二硫交换使Trx处于还原状态，从而阻止其与ASK1分离。本研究描述了一种以前未定义的机制，通过该机制，氧化还原敏感分子通过凋亡途径响应DA神经元中pd相关的毒性应激。我们的研究结果也提示PRX2和ASK1可能是PD神经保护干预的潜在靶点。
The peroxiredoxin (PRX) family of antioxidant enzymes helps maintain the intracellular reducing milieu and suppresses apoptosis in non-neuronal cells. However, whether PRX can inhibit neuronal apoptosis through specific signaling mechanisms remains poorly understood. Induction of PRX2, the most abundant neuronal PRX, occurs in Parkinson’s disease (PD) patient brains, but its functional impact is unclear. In the present study, we used the dopaminergic (DA) toxin 6-hydroxydopamine (6-OHDA) to model PD and explore the protective effect and mechanisms of PRX on DA neurons. Of the 2-cysteine PRXs that were tested in MN9D DA neurons, endogenous PRX2 was most beneficial to cell survival. Lentivirus-mediated PRX2 over-expression conferred marked in vitro and in vivo neuroprotection against 6-OHDA toxicity in DA neurons, and preserved motor functions involving the dopamine system in mouse. In addition to its role as an antioxidant enzyme, PRX2 exhibited anti-apoptotic effects in DA neurons via suppression of ASK1-dependent activation of the JNK/c-Jun and p38 pro-death pathways, which are also activated in DA neurons of post-mortem PD brains. PRX2 inhibited 6-OHDA-induced ASK1 activation by modulating the redox status of the endogenous ASK1 inhibitor thioredoxin (Trx). PRX2 over-expression maintained Trx in a reduced state by inhibiting the cysteine thiol-disulfide exchange, thereby preventing its dissociation from ASK1. This study describes a previously undefined mechanism by which redox-sensitive molecules signal via apoptotic pathways in response to PD-relevant toxic stress in DA neurons. Our results also suggest that PRX2 and ASK1 may be potential targets for neuroprotective intervention in PD.