Department of Medical Neurobiology, Hadassah Faculty of Medicine, The Hebrew University of Jerusalem Jerusalem, Israel.
Front Mol Neurosci. 2013 May 13;6:10. doi: 10.3389/fnmol.2013.00010. eCollection 2013.
MicroRNAs (miRNAs) are key post transcriptional regulators of their multiple target genes. However, the detailed profile of miRNA expression in Parkinson's disease, the second most common neurodegenerative disease worldwide and the first motor disorder has not been charted yet. Here, we report comprehensive miRNA profiling by next-generation small-RNA sequencing, combined with targets inspection by splice-junction and exon arrays interrogating leukocyte RNA in Parkinson's disease patients before and after deep brain stimulation (DBS) treatment and of matched healthy control volunteers (HC). RNA-Seq analysis identified 254 miRNAs and 79 passenger strand forms as expressed in blood leukocytes, 16 of which were modified in patients pre-treatment as compared to HC. 11 miRNAs were modified following brain stimulation 5 of which were changed inversely to the disease induced changes. Stimulation cessation further induced changes in 11 miRNAs. Transcript isoform abundance analysis yielded 332 changed isoforms in patients compared to HC, which classified brain transcriptomes of 47 PD and control independent microarrays. Functional enrichment analysis highlighted mitochondrion organization. DBS induced 155 splice changes, enriched in ubiquitin homeostasis. Cellular composition analysis revealed immune cell activity pre and post treatment. Overall, 217 disease and 74 treatment alternative isoforms were predictably targeted by modified miRNAs within both 3' and 5' untranslated ends and coding sequence sites. The stimulation-induced network sustained 4 miRNAs and 7 transcripts of the disease network. We believe that the presented dynamic networks provide a novel avenue for identifying disease and treatment-related therapeutic targets. Furthermore, the identification of these networks is a major step forward in the road for understanding the molecular basis for neurological and neurodegenerative diseases and assessment of the impact of brain stimulation on human diseases.
微小 RNA（miRNAs）是其多个靶基因的关键转录后调控因子。然而，在帕金森病（全球第二常见的神经退行性疾病，也是第一种运动障碍疾病）中，miRNA 的表达详细情况尚未得到阐明。在这里，我们报告了通过下一代小 RNA 测序进行的综合 miRNA 分析，结合了通过拼接接头和外显子阵列对帕金森病患者和匹配的健康对照志愿者（HC）的白细胞 RNA 进行的靶标检测。RNA-Seq 分析确定了 254 个 miRNA 和 79 个过客链形式在血液白细胞中表达，其中 16 个在患者治疗前与 HC 相比发生改变。11 个 miRNA 在大脑刺激后发生改变，其中 5 个与疾病诱导的变化相反。刺激停止后，进一步引起 11 个 miRNA 的变化。转录本亚型丰度分析显示与 HC 相比，患者中有 332 个亚型发生改变，将 47 个 PD 和对照独立微阵列的脑转录组分类。功能富集分析突出了线粒体组织。DBS 诱导了 155 个剪接变化，富含泛素稳态。细胞组成分析显示治疗前后免疫细胞的活性。总体而言，217 个疾病和 74 个治疗替代异构体在 3'和 5'非翻译区和编码序列位点被修饰的 miRNA 预测性靶向。刺激诱导的网络维持了疾病网络中的 4 个 miRNA 和 7 个转录物。我们认为，所呈现的动态网络为识别疾病和治疗相关的治疗靶点提供了新的途径。此外，这些网络的识别是理解神经和神经退行性疾病的分子基础以及评估脑刺激对人类疾病影响的重要一步。
