Modified level of miR-376a is associated with Parkinson's disease
Modified level of miR-376a is associated with Parkinson's disease
复制标题
DOI：
10.1111/jcmm.14979
复制
发表时间：
2020-01-12
影响因子：
5.3
通讯作者：
Ghaedi, Kamran
中科院分区：
文献类型：
--
作者：
Baghi, Masoud;Delavar, Mahsa Rostamian;Ghaedi, Kamran
帕金森病（PD）是一种常见的进行性神经退行性疾病。线粒体功能受损是散发性PD的主要特征。在PD中检测到的一些易感性或致病基因与线粒体功能障碍密切相关，包括PGC 1 α、TFAM和GSK 3 β。microRNA（miRNAs）是非编码RNA，其改变的水平在不同的PD模型和人脑中得到证实。因此，本研究的目的是检测与PD发作和进展相关的PGC 1 α、TFAM和GSK 3 β上游miR的调节。在本研究中，共招募了33名PD受试者和25名健康志愿者。通过靶点预测工具和文献调查筛选候选miRNA（miR-376 a）。慢性和急性体外PD模型由MPP+中毒SHSY 5 Y细胞产生。通过RT-qPCR评估miR-376 a和上述基因的水平。慢性模型中靶基因的表达下降，而急性PD模型中这些基因的表达水平显着上调。miR-376 a在急性和慢性PD模型以及PD患者的PBMC中均发生强烈改变。我们的研究结果还显示，PBMC中PGC 1 α和TFAM的过表达与miR-376 a的下调呈负相关，表明miR-376 a可能通过调节这些参与线粒体功能的基因对PD发病机制产生影响。PD来源的PBMC中的miR-376 a表达也与疾病严重程度相关，并且可以作为PD诊断的潜在生物标志物。这是第一项显示PD模型和PBMC中miR-376 a水平改变的研究，表明该miRNA在PD发病机制中可能起作用。本研究还首次提出TFAM和PGC 1 α为miR-376 a的靶基因，可能通过其对PD发病机制发挥作用。
Parkinson's disease (PD) is a frequent progressive neurodegenerative disorder. Impaired mitochondrial function is a major feature of sporadic PD. Some susceptibility or causative genes detected in PD are strongly associated with mitochondrial dysfunction including PGC1 alpha, TFAM and GSK3 beta. microRNAs (miRNAs) are non-coding RNAs whose altered levels are proven in disparate PD models and human brains. Therefore, the aim of this study was to detect modulations of miRs upstream of PGC1 alpha, TFAM and GSK3 beta in association with PD onset and progress. In this study, a total of 33 PD subjects and 25 healthy volunteers were recruited. Candidate miRNA (miR-376a) was selected through target prediction tools and literature survey. Chronic and acute in vitro PD models were created by MPP+-intoxicated SHSY5Y cells. The levels of miR-376a and aforementioned genes were assessed by RT-qPCR. The expression of target genes was decreased in chronic model while there were dramatically up-regulated levels of those genes in acute model of PD. miR-376a was strongly altered in both acute and chronic PD models as well as PBMCs of PD patients. Our results also showed overexpression of PGC1 alpha, and TFAM in PBMCs is inversely correlated with down-regulation of miR-376a, suggesting that miR-376a possibly has an impact on PD pathogenesis through regulation of these genes which are involved in mitochondrial function. miR-376a expression in PD-derived PBMCs was also correlated with disease severity and may serve as a potential biomarker for PD diagnosis. This is the first study showing altered levels of miR-376a in PD models and PBMCs, suggesting the probable role of this miRNA in PD pathogenesis. The present study also proposed TFAM and PGC1 alpha as target genes of miR-376a for the first time, through which it possibly can exert its impact on PD pathogenesis.