Early activation of Egr-1 promotes neuroinflammation and dopaminergic neurodegeneration in an experimental model of Parkinson's disease.
Early activation of Egr-1 promotes neuroinflammation and dopaminergic neurodegeneration in an experimental model of Parkinson's disease.
复制标题
在帕金森病的实验模型中，Egr-1 的早期激活会促进神经炎症和多巴胺能神经变性。
DOI：
10.1016/j.expneurol.2018.01.009
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Ma Shanshan
中科院分区：
文献类型：
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作者：
Yu Qing;Huang Qiaoying;Du Xiaoxiao;Xu Shao;Li Mingtao;Ma Shanshan
黑质多巴胺能神经元的进行性丢失是帕金森病（PD）的标志之一。已经提出神经炎症有助于疾病的进行性。早期生长反应-1（Egr-1）是一种锌指转录因子，已被证明在神经元死亡和炎症反应中起关键作用。然而，Egr-1是否以及如何参与PD的发病机制尚未研究。采用1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的亚急性PD小鼠模型，在黑质AldoC（+）星形胶质细胞的胞核中发现了Egr-1的早期高峰，而在纹状体中没有发现。通过光神霉素A对Egr-1进行基因切除或抑制其转录活性可显着抑制星形胶质细胞和小胶质细胞的激活，减少促炎细胞因子的表达，并保护SNpc中的多巴胺能细胞体免受变性。综上所述，这些发现表明，诱导Egr-1促进神经炎症和多巴胺能细胞体的损失在SNPC的MPTP诱导的小鼠模型，表明星形胶质细胞Egr-1在PD的神经炎症中的重要作用。
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 situimmunofluorescent 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.