Pittsburgh Institute of Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
J Neurosci. 2011 Jan 5;31(1):247-61. doi: 10.1523/JNEUROSCI.4589-10.2011.
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 overexpression 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 apoptosis signal-regulating kinase (ASK1)-dependent activation of the c-Jun N-terminal kinase/c-Jun and p38 pro-death pathways, which are also activated in DA neurons of postmortem PD brains. PRX2 inhibited 6-OHDA-induced ASK1 activation by modulating the redox status of the endogenous ASK1 inhibitor thioredoxin (Trx). PRX2 overexpression 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.
过氧化物酶（PRX）家族的抗氧化酶有助于维持细胞内的还原环境，并抑制非神经元细胞的细胞凋亡。然而，PRX 是否可以通过特定的信号机制抑制神经元细胞凋亡尚不清楚。帕金森病（PD）患者大脑中诱导 PRX2（最丰富的神经元 PRX）的发生，但功能影响尚不清楚。在本研究中，我们使用多巴胺（DA）毒素 6-羟多巴胺（6-OHDA）来模拟 PD 并探讨 PRX 对 DA 神经元的保护作用及其机制。在 MN9D DA 神经元中测试的 2-半胱氨酸 PRX 中，内源性 PRX2 对细胞存活最有益。慢病毒介导的 PRX2 过表达在体外和体内对 6-OHDA 诱导的 DA 神经元毒性均具有显著的保护作用，并能维持涉及多巴胺系统的运动功能。除了作为抗氧化酶的作用外，PRX2 通过抑制凋亡信号调节激酶（ASK1）依赖性 c-Jun N 末端激酶/c-Jun 和 p38 促死亡途径的激活，在 DA 神经元中表现出抗细胞凋亡作用，这也在 PD 患者死后大脑的 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）的氧化还原状态来抑制 6-OHDA 诱导的 ASK1 激活。PRX2 过表达通过抑制半胱氨酸巯基-二硫键交换来保持 Trx 处于还原状态，从而防止其从 ASK1 解离。本研究描述了一种以前未定义的机制，即氧化还原敏感分子通过凋亡途径在 DA 神经元中对与 PD 相关的毒性应激做出反应。我们的研究结果还表明，PRX2 和 ASK1 可能是 PD 神经保护干预的潜在靶点。
