Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte
Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte
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DOI：
10.1073/pnas.0813361106
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发表时间：
2009-02-24
影响因子：
11.1
通讯作者：
Johnson, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Chen, Pei-Chun;Vargas, Marcelo R.;Johnson, Jeffrey A.
氧化应激与帕金森病（PD）的病因学和PD的1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）动物模型有关。已知在氧化应激条件下，转录因子NF-E2相关因子（Nrf 2）与抗氧化反应元件（ARE）结合以诱导抗氧化和II相解毒酶。为了研究Nrf 2在MPTP诱导的毒性过程中的作用，使用表达由包含核心ARE序列的启动子驱动的人胎盘碱性磷酸酶（hPAP）基因（ARE-hPAP）的小鼠。ARE-hPAP小鼠每天注射（30 mg/kg）一次，持续5天，并在最后一次MPTP注射后7天处死。在这种设计中，ARE依赖的基因表达在纹状体中减少，而在黑质中增加。在Nrf 2（+/+）和Nrf 2（-/-）小鼠中应用相同的MPTP方案; Nrf 2缺陷增加MPTP敏感性。此外，我们评估了星形胶质细胞Nrf 2过表达保护MPTP毒性的潜力。在Nrf 2（+/+）和Nrf 2（-/-）背景下，Nrf 2在星形胶质细胞特异性胶质细胞酸性蛋白启动子（GFAP-Nrf 2）控制下的转基因小鼠被施用MPTP。在后一种情况下，只有星形胶质细胞表达Nrf 2。独立于背景，MPTP介导的毒性在GFAP-Nrf 2小鼠中被消除。这些惊人的结果表明，Nrf 2表达局限于星形胶质细胞足以保护免受MPTP和星形胶质细胞调节Nrf 2-ARE途径是一个有前途的目标，治疗旨在减少或预防神经元死亡的PD。
Oxidative stress has been implicated in the etiology of Parkinson's disease (PD) and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD. It is known that under conditions of oxidative stress, the transcription factor NF-E2-related factor (Nrf2) binds to antioxidant response element (ARE) to induce antioxidant and phase II detoxification enzymes. To investigate the role of Nrf2 in the process of MPTP-induced toxicity, mice expressing the human placental alkaline phosphatase (hPAP) gene driven by a promoter containing a core ARE sequence (ARE-hPAP) were used. ARE-hPAP mice were injected (30 mg/kg) once per day for 5 days and killed 7 days after the last MPTP injection. In response to this design, ARE-dependent gene expression was decreased in striatum whereas it was increased in substantia nigra. The same MPTP protocol was applied in Nrf2(+/+) and Nrf2(-/-) mice; Nrf2 deficiency increases MPTP sensitivity. Furthermore, we evaluated the potential for astrocytic Nrf2 overexpression to protect from MPTP toxicity. Transgenic mice with Nrf2 under control of the astrocyte-specific promoter for the glial fribillary acidic protein (GFAP-Nrf2) on both a Nrf2(+/+) and Nrf2(-/-) background were administered MPTP. In the latter case, only the astrocytes expressed Nrf2. Independent of background, MPTP-mediated toxicity was abolished in GFAP-Nrf2 mice. These striking results indicate that Nrf2 expression restricted to astrocytes is sufficient to protect against MPTP and astrocytic modulation of the Nrf2-ARE pathway is a promising target for therapeutics aimed at reducing or preventing neuronal death in PD.