MPTP selectively induces haem oxygenase-1 expression in striatal astrocytes
MPTP selectively induces haem oxygenase-1 expression in striatal astrocytes
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DOI：
10.1046/j.1460-9568.2000.00044.x
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发表时间：
2000-05-01
影响因子：
3.4
通讯作者：
Morgan, JI
中科院分区：
文献类型：
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作者：
Fernandez-Gonzalez, A;Pérez-Otaño, I;Morgan, JI
帕金森病 (PD) 的特征是黑质致密部多巴胺能神经元的丧失，并伴有氧化损伤增加、线粒体功能缺陷和铁沉积的证据。最近，据报道 PD 大脑中血红素加氧酶 1 水平升高。由于这种酶参与对氧化应激的反应，并且对于细胞血红素和铁稳态至关重要，因此它可能在帕金森病的发病机制中发挥作用。因此，我们研究了血红素加氧酶异构体 1 (HO-1) 在 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 小鼠 PD 模型中的表达。 MPTP 仅在小鼠纹状体中引发 HO-1 mRNA 相对快速且持续的增加。原位杂交和免疫组织化学显示 HO-1 定位于纹状体星形胶质细胞。 MPTP 对 HO-1 的诱导被司来吉兰和 GBR-12909 阻断，表明原毒素必须通过单胺氧化酶 B 代谢并被多巴胺能神经元吸收才能在星形胶质细胞中发挥作用。 MPTP 不会改变血红素合成或降解的其他酶的表达，也不会改变血红素或铁结合蛋白的 mRNA 水平。因此，HO-1 的表达不是涉及血红素生物合成或稳态的细胞程序的一部分。此外，MPTP 不诱导热休克蛋白。因此，MPTP 在纹状体星形胶质细胞中引发选择性转录反应。这种反应似乎是由纹状体中受影响的多巴胺能神经末梢释放的分子介导的，作用于邻近的星形胶质细胞。讨论了该信号通路及其与 PD 的潜在相关性。
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta with accompanying evidence of increased oxidative damage, deficits in mitochondrial function and iron deposition. Recently, haem oxygenase-1 levels were reported to be elevated in PD brains. Because this enzyme is involved in the response to oxidative stress and is critical for cellular haem and iron homeostasis, it could play a role in the pathogenesis of PD. Therefore, we investigated the expression of haem oxygenase isoform 1 (HO-1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP triggered a relatively rapid and persistent increase in HO-1 mRNA exclusively in the mouse striatum. In situ hybridization and immunohistochemistry showed HO-1 to be localized to striatal astrocytes. The induction of HO-1 by MPTP was blocked by selegiline and GBR-12909, indicating the protoxin had to be metabolized by monoamine oxidase B and taken up by dopaminergic neurons to exert its action in astrocytes. MPTP did not alter the expression of other enzymes of haem synthesis or degradation nor were the levels of mRNA for haem or iron-binding proteins changed. Thus, expression of HO-1 was not part of a cellular program involving haem biosynthesis or homeostasis. In addition, heat shock proteins were not induced by MPTP. Thus, MPTP elicited a selective transcriptional response in striatal astrocytes. This response appears to be mediated by molecules released from affected dopaminergic nerve terminals in the striatum acting upon neighbouring astrocytes. This signalling pathway and its potential relevance to PD are discussed.