Up-regulation of autophagy-related gene 5 (ATG5) protects dopaminergic neurons in a zebrafish model of Parkinson's disease
Up-regulation of autophagy-related gene 5 (ATG5) protects dopaminergic neurons in a zebrafish model of Parkinson's disease
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DOI：
10.1074/jbc.m116.764795
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发表时间：
2017-11-03
影响因子：
4.8
通讯作者：
Ma, Yuan-yuan
中科院分区：
文献类型：
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作者：
Hu, Zhan-ying;Chen, Bo;Ma, Yuan-yuan
帕金森病（Parkinson's disease，PD）是一种流行性神经退行性疾病，其特征是中脑多巴胺能（dopaminergic，DA）神经元的缺失引起的运动障碍。最近，PD和自噬之间的关系受到了相当大的关注，但有关其机制的信息还很缺乏。在这里，我们报告，自噬相关基因5（ATG 5）是潜在的重要保护多巴胺能神经元在1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的PD模型在斑马鱼。通过对斑马鱼游泳行为、原位杂交、免疫荧光以及与PD和自噬相关的基因和蛋白表达的分析，我们发现在该模型中，ATG 5表达水平降低，自噬通量被阻断。在斑马鱼模型中，ATG 5下调导致PD相关蛋白（如-突触核蛋白、Parkin和PINK 1）的升级，MPTP诱导的PD模拟病理运动行为的加重，酪氨酸羟化酶（TH）或多巴胺转运蛋白（DAT）标记的DA神经元丢失，并阻断自噬通量。ATG 5过表达减轻或逆转了这些PD病理特征，拯救了DA神经元细胞，如升高的TH/DAT水平所示，并恢复了自噬通量。ATG 5在保护DA神经元中的作用通过人atg 5基因在斑马鱼模型中的表达得到证实。我们的研究结果表明，ATG 5具有神经保护作用，ATG 5的上调可能成为PD预防和管理药物开发的目标。
Parkinson's disease (PD) is one of the most epidemic neurodegenerative diseases and is characterized by movement disorders arising from loss of midbrain dopaminergic (DA) neurons. Recently, the relationship between PD and autophagy has received considerable attention, but information about the mechanisms involved is lacking. Here, we report that autophagy-related gene 5 (ATG5) is potentially important in protecting dopaminergic neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in zebrafish. Using analyses of zebrafish swimming behavior, in situ hybridization, immunofluorescence, and expressions of genes and proteins related to PD and autophagy, we found that the ATG5 expression level was decreased and autophagy flux was blocked in this model. The ATG5 down-regulation led to the upgrade of PD-associated proteins, such as -synuclein, Parkin, and PINK1, aggravation of MPTP-induced PD-mimicking pathological locomotor behavior, DA neuron loss labeled by tyrosine hydroxylase (TH) or dopamine transporter (DAT), and blocked autophagy flux in the zebrafish model. ATG5 overexpression alleviated or reversed these PD pathological features, rescued DA neuron cells as indicated by elevated TH/DAT levels, and restored autophagy flux. The role of ATG5 in protecting DA neurons was confirmed by expression of the human atg5 gene in the zebrafish model. Our findings reveal that ATG5 has a role in neuroprotection, and up-regulation of ATG5 may serve as a goal in the development of drugs for PD prevention and management.