Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, No. 74 Zhongshan Rd. 2, Guangzhou 510080, China.
Exp Neurol. 2018 Apr;302:145-154. doi: 10.1016/j.expneurol.2018.01.009. Epub 2018 Jan 11.
The progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is one of the hallmarks of Parkinson's disease (PD). Neuroinflammation has been proposed to contributes to the progressive nature of the disease. Early growth response-1 (Egr-1), a zinc finger transcription factor, has been shown to have a crucial role in both neuronal death and the inflammatory response. However, whether and how Egr-1 is involved in the pathogenesis of PD has not been investigated. Using the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, we identified early peak induction of Egr-1 in the SNpc but not in the striatum. In situ immunofluorescent analysis showed that Egr-1 predominantly locates in the nuclei of nigral AldoC (+) astrocytes upon MPTP treatment. Genetic ablation of Egr-1 or inhibition of its transcriptional activity by Mithramycin A significantly suppresses the activation of both astrocytes and microglia, decreases proinflammatory cytokine expression, and protects dopaminergic cell bodies from degeneration in the SNpc. Taken together, these findings demonstrate that the induction of Egr-1 promotes neuroinflammation and dopaminergic cell body loss in the SNpc of MPTP-induced mouse model, suggesting an important role of astrocytic Egr-1 in neuroinflammation in PD.
黑质致密部多巴胺能神经元的进行性丧失是帕金森病（PD）的标志之一。神经炎症被认为是导致疾病进行性发展的原因之一。早期生长反应因子-1（Egr-1）是一种锌指转录因子，它在神经元死亡和炎症反应中都起着至关重要的作用。然而，Egr-1 是否以及如何参与 PD 的发病机制尚未得到研究。我们使用亚急性 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠模型，发现 Egr-1 在 SNpc 中而不是纹状体中早期出现高峰诱导。原位免疫荧光分析显示，Egr-1 在 MPTP 处理后主要位于黑质 AldoC（+）星形胶质细胞的细胞核中。Egr-1 的基因缺失或米托蒽醌 A 抑制其转录活性显著抑制了星形胶质细胞和小胶质细胞的激活，降低了促炎细胞因子的表达，并保护 SNpc 中的多巴胺能神经元免受变性。综上所述，这些发现表明 Egr-1 的诱导促进了 MPTP 诱导的小鼠模型中 SNpc 的神经炎症和多巴胺能神经元体的丧失，提示星形胶质细胞 Egr-1 在 PD 中的神经炎症中起重要作用。
