Lee Myung Ae, Lee Hye-Souk, Lee Hyun Soo, Cho Kyung G, Jin Byung Kwan, Sohn Seonghyang, Lee Young Seek, Ichinose Hiroshi, Kim Seung Up
Brain Disease Research Center, Ajou University School of Medicine, Suwon, South Korea.
Neurosci Lett. 2002 Nov 15;333(1):74-8. doi: 10.1016/s0304-3940(02)00981-3.
Nurr1 is a member of the nuclear receptor superfamily of transcription factors that is highly expressed in midbrain dopaminergic (DA) neurons, the cells primarily lost in human Parkinson's disease (PD), and in Nurr1-null mice selective agenesis of midbrain DA neurons is found. To investigate possible correlation between the expression of Nurr1 gene and neurotoxin-induced cell death of DA neurons, a neural stem cell line (NSC, A3) and Nurr1-overexpressing NSC (A3.Nurr1) were exposed to DA neurotoxins 6-hydroxydopamine (6-OHDA) and methyl phenylpyridinium (MPP(+)). Although both neurotoxins were shown to induce cell death in A3 and A3.Nurr1 cells, patterns of cell deaths were different. A3.Nurr1 cells showed increased vulnerability to 6-OHDA cytotoxicity, but increased resistance to MPP(+)-induced cell death when compared to A3 cells. To investigate the differential vulnerability to neurotoxins by Nurr1 protein correlates with biochemical features that discriminate between apoptosis and necrosis, we carried out a nucleosomal DNA fragmentation assay and electron microscopy. While 6-OHDA treatment induced shrinkage of cytoplasmic membrane, condensation of nuclei and generation of apoptotic bodies in both cell lines, cells treated with MPP(+) showed mitochondrial swelling, indicating that 6-OHDA- but not MPP(+)-mediated cell death was apoptotic. These results suggest that DA neuronal cell death in response to 6-OHDA and MPP(+) may progress through separate signaling pathways differentially regulated by the Nurr1 protein. Our observations indicated that Nurr1 may play a role in the manifestation of DA neurotoxicity and that variations in Nurr1 expression might be a susceptibility factor for DA neurodegeneration in PD.
Nurr1是转录因子核受体超家族的成员，在中脑多巴胺能（DA）神经元中高度表达，而中脑多巴胺能神经元是人类帕金森病（PD）中主要受损的细胞，并且在Nurr1基因缺失的小鼠中发现了中脑DA神经元的选择性发育不全。为了研究Nurr1基因表达与神经毒素诱导的DA神经元细胞死亡之间的可能相关性，将一种神经干细胞系（NSC，A3）和过表达Nurr1的NSC（A3.Nurr1）暴露于DA神经毒素6-羟基多巴胺（6-OHDA）和甲基苯基吡啶鎓（MPP(+)）。虽然两种神经毒素均显示可诱导A3和A3.Nurr1细胞死亡，但细胞死亡模式不同。与A3细胞相比，A3.Nurr1细胞对6-OHDA细胞毒性的敏感性增加，但对MPP(+)诱导的细胞死亡的抗性增加。为了研究Nurr1蛋白对神经毒素的不同敏感性是否与区分凋亡和坏死的生化特征相关，我们进行了核小体DNA片段化分析和电子显微镜检查。虽然6-OHDA处理在两种细胞系中均诱导了细胞质膜收缩、细胞核浓缩和凋亡小体的产生，但用MPP(+)处理的细胞显示出线粒体肿胀，表明6-OHDA介导而非MPP(+)介导的细胞死亡是凋亡性的。这些结果表明，对6-OHDA和MPP(+)作出反应的DA神经元细胞死亡可能通过由Nurr1蛋白差异调节的不同信号通路进行。我们的观察结果表明，Nurr1可能在DA神经毒性的表现中起作用，并且Nurr1表达的变化可能是PD中DA神经退行性变的一个易感因素。
