c-Jun/Bim Upregulation in Dopaminergic Neurons Promotes Neurodegeneration in the MPTP Mouse Model of Parkinson’s disease
c-Jun/Bim Upregulation in Dopaminergic Neurons Promotes Neurodegeneration in the MPTP Mouse Model of Parkinson’s disease
复制标题
多巴胺能神经元中的 c-Jun/Bim 上调促进帕金森病 MPTP 小鼠模型中的神经变性
DOI：
10.1016/j.neuroscience.2018.12.026
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发表时间：
2018
期刊：
影响因子：
3.3
通讯作者：
Shanshan Ma
中科院分区：
文献类型：
--
作者：
Kunhua Hu;Qiaoying Huang;Chong Liu;Yongyi Li;Yueyue Liu;Hao Wang;Mingtao Li;Shanshan Ma
帕金森病是一种常见的神经退行性疾病，以黑质致密部多巴胺能神经元进行性丢失为特征。据报道，促凋亡蛋白BH3-Only Bim参与了实验性帕金森病的多巴胺能神经变性。然而，Bim在帕金森病发病机制中的表达尚不清楚，Bim在帕金森病发病机制中的细胞类型尚不清楚。在这里，我们在情景观察中报告了在1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)处理的小鼠SNPC的多巴胺能神经元中转录诱导的BIM。为了研究Bim在帕金森病神经元死亡中在多巴胺能神经元中的确切作用，我们获得了多巴胺能神经元特异性Bimull(Bim Dat)小鼠。BIM数据小鼠被证明对MPTP诱导的神经毒性具有抵抗力，证实了BIM在多巴胺能神经元中的诱导是帕金森病神经变性的原因。此外，我们用多巴胺能神经元特异性c-jun基因敲除(c-jun Dat)证实了黑质多巴胺能神经元Bim的转录上调是c-jun依赖的，进一步证实了c-jun在多巴胺能神经退行性变中的不利作用。综上所述，这些数据表明，c-jun介导的Bim在黑质多巴胺能神经元中上调有助于帕金森病神经退行性变。
Parkinson’s disease (PD) is a common neurodegenerative disease that is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The proapoptotic BH3-only protein Bim has been reported to be involved in dopaminergic neurodegeneration of experimental PD. However, anin situexpression profile of Bim in PD has not been performed, and the cell types of which Bim accounts for PD pathogenesis is unclear. Here, we report within situobservations that Bim is transcriptionally induced in the dopaminergic neurons of the SNpc in 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. To investigate the precise role of Bim in the dopaminergic neurons in parkinsonian neuronal death, we obtained dopaminergic neuron-specificBimnull (Bim△Dat) mice. Bim△Datmice are shown to be resistant to MPTP-induced neurotoxicity, confirming that the induction of Bim in dopaminergic neurons is responsible for parkinsonian neurodegeneration. Furthermore, we demonstrated with dopaminergic neuron-specific c-Junknockout (c-Jun△Dat) that the transcriptional upregulation of Bim of nigral dopaminergic neurons was c-Jun-dependent and further validated the detrimental role of c-Jun in dopaminergic neurodegeneration. Together, these data specify that c-Jun-mediated Bim upregulation in nigral dopaminergic neurons contributes to parkinsonian neurodegeneration.