Molecular BioSciences, University of Frankfurt, Marie-Curie-Str.9, 60439 Frankfurt a.M., Germany.
Transl Neurodegener. 2014 Aug 18;3:17. doi: 10.1186/2047-9158-3-17. eCollection 2014.
Non-coding RNAs (ncRNAs) play various roles during central nervous system development. MicroRNAs (miRNAs) are a class of ncRNAs that exert their function together with argonaute proteins by post-transcriptional gene silencing of messenger RNAs (mRNAs). Several studies provide evidence for alterations in miRNA expression in patients with neurodegenerative diseases. Among these is huntington's disease (HD), a dominantly inherited fatal disorder characterized by deregulation of neuronal-specific mRNAs as well as miRNAs. Recently, next-generation sequencing (NGS) miRNA profiles from human HD and neurologically normal control brain tissues were reported. Five consistently upregulated miRNAs affect the expression of genes involved in neuronal differentiation, neurite outgrowth, cell death and survival. We re-analyzed the NGS data publicly available in array express and detected nineteen additional differentially expressed miRNAs. Subsequently, we connected these miRNAs to genes implicated in HD development and network analysis pointed to miRNA-mediated downregulation of twenty-two genes with roles in the pathogenesis as well as treatment of the disease. In silico prediction and reporter systems prove that levels of BDNF, a central node in the miRNA-mRNA regulatory network, can be post-transcriptionally controlled by upregulated miR-10b-5p and miR-30a-5p. Reduced BDNF expression is associated with neuronal dysfunction and death in HD. Moreover, the 3'UTR of CREB1 harbors a predicted binding site for these two miRNAs. CREB1 is similarly downregulated in HD and overexpression decreased susceptibility to 3-nitropropionic-induced toxicity in a cell model. In contradiction to these observations, it is presumed that miR-10b-5p upregulation in HD exerts a neuroprotective role in response to the mutation in the huntingtin gene. Therefore, the function of miR-10b-5p and especially its effect on BDNF expression in HD requires further academic research.
非编码 RNA（ncRNA）在中枢神经系统发育过程中发挥多种作用。微小 RNA（miRNA）是一类 ncRNA，通过信使 RNA（mRNA）的转录后基因沉默与 Argonaute 蛋白共同发挥作用。一些研究为神经退行性疾病患者 miRNA 表达改变提供了证据。其中包括亨廷顿病（HD），这是一种显性遗传的致命疾病，其特征是神经元特异性 mRNA 以及 miRNA 的失调。最近，报道了来自人类 HD 和神经正常对照脑组织的下一代测序（NGS）miRNA 图谱。五种一致上调的 miRNA 影响参与神经元分化、神经突生长、细胞死亡和存活的基因的表达。我们重新分析了 array express 上公开的 NGS 数据，并检测到另外 19 个差异表达的 miRNA。随后，我们将这些 miRNA 与与 HD 发展相关的基因联系起来，网络分析表明 miRNA 介导了 22 个在疾病发病机制和治疗中起作用的基因的下调。基于计算机的预测和报告系统证明，BDNF（miRNA-mRNA 调控网络中的中心节点）的水平可以被上调的 miR-10b-5p 和 miR-30a-5p 进行转录后调控。BDNF 表达降低与 HD 中的神经元功能障碍和死亡有关。此外，CREB1 的 3'UTR 包含这两个 miRNA 的预测结合位点。在 HD 中，CREB1 也被下调，在细胞模型中过表达会降低对 3-硝基丙酸诱导毒性的敏感性。与这些观察结果相反，据推测，HD 中 miR-10b-5p 的上调是对亨廷顿基因突变的一种神经保护作用。因此，miR-10b-5p 的功能，特别是其在 HD 中对 BDNF 表达的影响，需要进一步的学术研究。
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