Genetic Causes of Disease Group; Centre for Genomic Regulation (CRG); Barcelona, Spain; Universitat Pompeu Fabra (UPF); Barcelona, Spain; Universitat de Barcelona; Barcelona, Spain.
RNA Biol. 2013 Jul;10(7):1093-106. doi: 10.4161/rna.24813. Epub 2013 May 1.
MicroRNAs (miRNAs) and other small non-coding RNAs (sncRNAs) are post-transcriptional regulators of gene expression, playing key roles in neuronal development, plasticity, and disease. Transcriptome deregulation caused by miRNA dysfunction has been associated to neurodegenerative diseases. Parkinson disease (PD) is the second most common neurodegenerative disease showing deregulation of the coding and small non-coding transcriptome. On profiling sncRNA in PD brain areas differently affected, we found that upregulation of a small vault RNA (svtRNA2-1a) is widespread in PD brains, occurring early in the course of the disease (at pre-motor stages). SvtRNA2-1a biogenesis was dependent on Dicer activity on its precursor (vtRNA2-1) but independent of Drosha endonuclease, unlike the canonical miRNAs. Although endogenous svtRNA2-1a was enriched in Ago-2 immunoprecipitates in differentiated SH-SY5Y neuronal cells, overexpression of svtRNA2-1a induced subtle transcriptomic changes, suggesting that gene expression regulation may involve other mechanisms than mRNA decay only. Function enrichment analysis of the genes deregulated by svtRNA2-1a overexpression or svtRNA2-1a predicted targets identified pathways related to nervous system development and cell type specification. The expression pattern of svtRNA2-1a during development and aging of the human brain and the detrimental consequences of a svtRNA2-1a mimic overexpression in neuronal cells further indicate that low svtRNA2-1a levels may be important for the maintenance of neurons. Our results suggest that early svtRNA2-1a upregulation in PD may contribute to perturbations of gene expression networks, underlying metabolic impairment and cell dysfunction. A better understanding of the pathways regulated by svtRNA2-a, and also the mechanisms regulating its expression should facilitate the identification of new targets for therapeutic approaches in PD.
微小 RNA（miRNAs）和其他小非编码 RNA（sncRNAs）是基因表达的转录后调控因子，在神经元发育、可塑性和疾病中发挥关键作用。miRNA 功能障碍引起的转录组失调与神经退行性疾病有关。帕金森病（PD）是第二常见的神经退行性疾病，其编码和小非编码转录组均出现失调。在对不同受影响的 PD 脑区的 sncRNA 进行分析时，我们发现一种小 vault RNA（svtRNA2-1a）的上调在 PD 脑中广泛存在，并且发生在疾病的早期（运动前阶段）。svtRNA2-1a 的生物发生依赖于其前体（vtRNA2-1）上的 Dicer 活性，但与经典 miRNA 不同，它不依赖于 Drosha 内切酶。尽管内源性 svtRNA2-1a 在分化的 SH-SY5Y 神经元细胞中的 Ago-2 免疫沉淀物中富集，但 svtRNA2-1a 的过表达仅诱导了微妙的转录组变化，这表明基因表达调控可能涉及除 mRNA 降解以外的其他机制。svtRNA2-1a 过表达或 svtRNA2-1a 预测靶标调控的基因的功能富集分析确定了与神经系统发育和细胞类型特化相关的途径。svtRNA2-1a 在人类大脑发育和衰老过程中的表达模式以及 svtRNA2-1a 模拟物过表达对神经元细胞的有害后果进一步表明，svtRNA2-1a 水平较低可能对神经元的维持很重要。我们的结果表明，PD 中早期 svtRNA2-1a 的上调可能导致基因表达网络的紊乱，从而导致代谢损伤和细胞功能障碍。更好地了解 svtRNA2-a 调控的途径以及调节其表达的机制，应有助于确定 PD 治疗方法的新靶点。
