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对脑 miRNA 和 mRNA 表达谱的分析揭示了一个受突变型 huntingtin 扰乱的分子调控网络。

Interrogation of brain miRNA and mRNA expression profiles reveals a molecular regulatory network that is perturbed by mutant huntingtin.

机构信息

Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

出版信息

J Neurochem. 2012 Nov;123(4):477-90. doi: 10.1111/j.1471-4159.2012.07925.x. Epub 2012 Sep 28.

Abstract

Emerging evidence indicates that microRNAs (miRNAs) may play an important role in the pathogenesis of Huntington's disease (HD). To identify the individual miRNAs that are altered in HD and may therefore regulate a gene network underlying mutant huntingtin-induced neuronal dysfunction in HD, we performed miRNA array analysis combined with mRNA profiling in the cerebral cortex from N171-82Q HD mice. Expression profiles of miRNAs as well as mRNAs in HD mouse cerebral cortex were analyzed and confirmed at different stages of disease progression; the most significant changes of miRNAs in the cerebral cortex were also detected in the striatum of HD mice. Our results revealed a significant alteration of miR-200 family members, miR-200a, and miR-200c in the cerebral cortex and the striatum, at the early stage of disease progression in N171-82Q HD mice. We used a coordinated approach to integrate miRNA and mRNA profiling, and applied bioinformatics to predict a target gene network potentially regulated by these significantly altered miRNAs that might be involved in HD disease progression. Interestingly, miR-200a and miR-200c are predicted to target genes regulating synaptic function, neurodevelopment, and neuronal survival. Our results suggest that altered expression of miR-200a and miR-200c may interrupt the production of proteins involved in neuronal plasticity and survival, and further investigation of the involvement of perturbed miRNA expression in HD pathogenesis is warranted, and may lead to reveal novel approaches for HD therapy.

摘要

新兴证据表明,微小 RNA(miRNA)可能在亨廷顿病(HD)的发病机制中发挥重要作用。为了确定在 HD 中发生改变的个体 miRNA,从而可能调节突变亨廷顿蛋白诱导的 HD 神经元功能障碍的基因网络,我们在 N171-82Q HD 小鼠的大脑皮层中进行了 miRNA 阵列分析与 mRNA 谱分析相结合的研究。在疾病进展的不同阶段分析和验证了 HD 小鼠大脑皮层中 miRNA 和 mRNA 的表达谱;还在 HD 小鼠的纹状体中检测到了大脑皮层中 miRNA 的最显著变化。我们的研究结果表明,在 N171-82Q HD 小鼠疾病进展的早期阶段,miR-200 家族成员 miR-200a 和 miR-200c 在大脑皮层和纹状体中发生了显著改变。我们使用整合 miRNA 和 mRNA 谱分析的协调方法,并应用生物信息学预测了这些显著改变的 miRNA 可能参与 HD 疾病进展的潜在靶基因网络。有趣的是,miR-200a 和 miR-200c 被预测靶向调节突触功能、神经发育和神经元存活的基因。我们的研究结果表明,miR-200a 和 miR-200c 的表达改变可能会干扰涉及神经元可塑性和存活的蛋白质的产生,进一步研究失调的 miRNA 表达在 HD 发病机制中的作用是有必要的,并且可能会揭示出治疗 HD 的新方法。

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