Aimé Pascaline, Sun Xiaotian, Zareen Neela, Rao Apeksha, Berman Zachary, Volpicelli-Daley Laura, Bernd Paulette, Crary John F, Levy Oren A, Greene Lloyd A
Departments of Pathology and Cell Biology and
Departments of Pathology and Cell Biology and.
J Neurosci. 2015 Jul 29;35(30):10731-49. doi: 10.1523/JNEUROSCI.0614-15.2015.
Parkinson's disease (PD) is characterized by the progressive loss of select neuronal populations, but the prodeath genes mediating the neurodegenerative processes remain to be fully elucidated. Trib3 (tribbles pseudokinase 3) is a stress-induced gene with proapoptotic activity that was previously described as highly activated at the transcriptional level in a 6-hydroxydopamine (6-OHDA) cellular model of PD. Here, we report that Trib3 immunostaining is elevated in dopaminergic neurons of the substantia nigra pars compacta (SNpc) of human PD patients. Trib3 protein is also upregulated in cellular models of PD, including neuronal PC12 cells and rat dopaminergic ventral midbrain neurons treated with 6-OHDA, 1-methyl-4-phenylpyridinium (MPP+), or α-synuclein fibrils (αSYN). In the toxin models, Trib3 induction is substantially mediated by the transcription factors CHOP and ATF4. Trib3 overexpression is sufficient to promote neuronal death; conversely, Trib3 knockdown protects neuronal PC12 cells as well as ventral midbrain dopaminergic neurons from 6-OHDA, MPP+, or αSYN. Mechanism studies revealed that Trib3 physically interacts with Parkin, a prosurvival protein whose loss of function is associated with PD. Elevated Trib3 reduces Parkin expression in cultured cells; and in the SNpc of PD patients, Parkin levels are reduced in a subset of dopaminergic neurons expressing high levels of Trib3. Loss of Parkin at least partially mediates the prodeath actions of Trib3 in that Parkin knockdown in cellular PD models abolishes the protective effect of Trib3 downregulation. Together, these findings identify Trib3 and its regulatory pathways as potential targets to suppress the progression of neuron death and degeneration in PD.
Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Current treatments ameliorate symptoms, but not the underlying neuronal death. Understanding the core neurodegenerative processes in PD is a prerequisite for identifying new therapeutic targets and, ultimately, curing this disease. Here, we describe a novel pathway involving the proapoptotic protein Trib3 in neuronal death associated with PD. These findings are supported by data from multiple cellular models of PD and by immunostaining of postmortem PD brains. Upstream, Trib3 is induced by the transcription factors ATF4 and CHOP; and downstream, Trib3 interferes with the PD-associated prosurvival protein Parkin to mediate death. These findings establish this new pathway as a potential and promising therapeutic target for treatment of PD.
帕金森病（PD）的特征是特定神经元群体的渐进性丧失，但介导神经退行性变过程的促死亡基因仍有待充分阐明。TRIB3（ Tribbles假激酶3）是一种具有促凋亡活性的应激诱导基因，先前在PD的6-羟基多巴胺（6-OHDA）细胞模型中被描述为在转录水平高度激活。在此，我们报告在人类PD患者黑质致密部（SNpc）的多巴胺能神经元中，TRIB3免疫染色升高。在PD的细胞模型中，包括神经元PC12细胞以及用6-OHDA、1-甲基-4-苯基吡啶鎓（MPP+）或α-突触核蛋白原纤维（αSYN）处理的大鼠多巴胺能腹侧中脑神经元中，TRIB3蛋白也上调。在毒素模型中，TRIB3的诱导主要由转录因子CHOP和ATF4介导。TRIB3过表达足以促进神经元死亡；相反，TRIB3敲低可保护神经元PC12细胞以及腹侧中脑多巴胺能神经元免受6-OHDA、MPP+或αSYN的损伤。机制研究表明，TRIB3与Parkin发生物理相互作用，Parkin是一种与生存相关的蛋白质，其功能丧失与PD有关。TRIB3升高会降低培养细胞中Parkin的表达；在PD患者的SNpc中，在表达高水平TRIB3的一部分多巴胺能神经元中，Parkin水平降低。Parkin的缺失至少部分介导了TRIB3的促死亡作用，因为在细胞PD模型中敲低Parkin可消除TRIB3下调的保护作用。总之，这些发现确定TRIB3及其调节途径是抑制PD中神经元死亡和变性进展的潜在靶点。
帕金森病（PD）是最常见的神经退行性运动障碍。目前的治疗可改善症状，但不能阻止潜在的神经元死亡。了解PD中的核心神经退行性变过程是确定新治疗靶点并最终治愈该疾病的先决条件。在此，我们描述了一条涉及促凋亡蛋白TRIB3的与PD相关的神经元死亡新途径。这些发现得到了来自多个PD细胞模型的数据以及PD死后大脑免疫染色的支持。在该途径上游，TRIB3由转录因子ATF4和CHOP诱导；在下游，TRIB3干扰与PD相关的生存蛋白Parkin以介导细胞死亡。这些发现确立了这条新途径作为治疗PD的潜在且有前景的治疗靶点。
