MicroRNA profiling of Parkinson's disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function
MicroRNA profiling of Parkinson's disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function
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DOI：
10.1093/hmg/ddr210
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发表时间：
2011-08-01
影响因子：
3.5
通讯作者：
Marti, Eulalia
中科院分区：
文献类型：
--
作者：
Minones-Moyano, Elena;Porta, Silvia;Marti, Eulalia
microRNAs（miRNAs）是一种转录后基因表达调控因子，在神经元发育、可塑性和疾病中发挥重要作用。帕金森病（PD）是第二常见的神经退行性疾病，其特征在于存在蛋白质内含物或路易体以及中脑中多巴胺能神经元的进行性损失。在这里，我们评估了PD脑样本中miRNA表达的失调。miRNA表达谱分析显示，在疾病的临床（运动）阶段（Braak 4和5期），包括杏仁核、额叶皮质、黑质和小脑，具有可变神经病理学影响的脑区域中miR-34 b和miR-34 c的表达降低。此外，在疾病的运动前阶段（1-3期）中检测到miR-34 b/c的失调，因此在生命期间未接受任何PD相关治疗的病例中也是如此。分化的SH-SY 5 Y多巴胺能神经元细胞中miR-34 b或miR-34 c的消耗导致细胞活力的中度降低，伴随着线粒体功能和动力学的改变、氧化应激和总细胞三磷酸腺苷含量的降低。miR-34 b/c下调与DJ 1和Parkin表达的减少相关联，这两种蛋白质与家族性PD相关，在特发性病例中也有作用。因此，在显示出强烈的miR-34 b/c下调的PD脑样品中，DJ 1和Parkin表达降低。我们认为，PD中miR-34 b/c的早期失调触发下游转录组改变，导致线粒体功能障碍和氧化应激，最终损害细胞活力。更好地理解控制和/或由miR-34 b/c控制的细胞途径应该允许识别用于开发治疗方法的靶点。
MicroRNAs (miRNAs) are post-transcriptional gene expression regulators, playing key roles in neuronal development, plasticity and disease. Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the presence of protein inclusions or Lewy bodies and a progressive loss of dopaminergic neurons in the midbrain. Here, we have evaluated miRNA expression deregulation in PD brain samples. MiRNA expression profiling revealed decreased expression of miR-34b and miR-34c in brain areas with variable neuropathological affectation at clinical (motor) stages (Braak stages 4 and 5) of the disease, including the amygdala, frontal cortex, substantia nigra and cerebellum. Furthermore, misregulation of miR-34b/c was detected in pre-motor stages (stages 1-3) of the disease, and thus in cases that did not receive any PD-related treatment during life. Depletion of miR-34b or miR-34c in differentiated SH-SY5Y dopaminergic neuronal cells resulted in a moderate reduction in cell viability that was accompanied by altered mitochondrial function and dynamics, oxidative stress and reduction in total cellular adenosin triphosphate content. MiR-34b/c downregulation was coupled to a decrease in the expression of DJ1 and Parkin, two proteins associated to familial forms of PD that also have a role in idiopathic cases. Accordingly, DJ1 and Parkin expression was reduced in PD brain samples displaying strong miR-34b/c downregulation. We propose that early deregulation of miR-34b/c in PD triggers downstream transcriptome alterations underlying mitochondrial dysfunction and oxidative stress, which ultimately compromise cell viability. A better understanding of the cellular pathways controlling and/or controlled by miR-34b/c should allow identification of targets for development of therapeutic approaches.