Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, Brazil.
CNRS UPR9022, Inserm U1257, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Strasbourg, France.
ASN Neuro. 2021 Jan-Dec;13:17590914211009857. doi: 10.1177/17590914211009857.
Huntington's disease (HD) is a genetic disorder marked by transcriptional alterations that result in neuronal impairment and death. MicroRNAs (miRNAs) are non-coding RNAs involved in post-transcriptional regulation and fine-tuning of gene expression. Several studies identified altered miRNA expression in HD and other neurodegenerative diseases, however their roles in early stages of HD remain elusive. Here, we deep-sequenced miRNAs from the striatum of the HD mouse model, BACHD, at the age of 2 and 8 months, representing the pre-symptomatic and symptomatic stages of the disease. Our results show that 44 and 26 miRNAs were differentially expressed in 2- and 8-month-old BACHD mice, respectively, as compared to wild-type controls. Over-representation analysis suggested that miRNAs up-regulated in 2-month-old mice control the expression of genes crucial for PI3K-Akt and mTOR cell signaling pathways. Conversely, miRNAs regulating genes involved in neuronal disorders were down-regulated in 2-month-old BACHD mice. Interestingly, primary striatal neurons treated with anti-miRs targeting two up-regulated miRNAs, miR-449c-5p and miR-146b-5p, showed higher levels of cell death. Therefore, our results suggest that the miRNAs altered in 2-month-old BACHD mice regulate genes involved in the promotion of cell survival. Notably, over-representation suggested that targets of differentially expressed miRNAs at the age of 8 months were not significantly enriched for the same pathways. Together, our data shed light on the role of miRNAs in the initial stages of HD, suggesting a neuroprotective role as an attempt to maintain or reestablish cellular homeostasis.
亨廷顿病（HD）是一种遗传性疾病，其特征是转录改变导致神经元损伤和死亡。microRNAs（miRNAs）是参与转录后调控和基因表达精细调节的非编码 RNA。几项研究已经确定了在 HD 和其他神经退行性疾病中miRNA 表达的改变，然而，它们在 HD 的早期阶段的作用仍不清楚。在这里，我们对 HD 小鼠模型 BACHD 的纹状体中的 miRNA 进行了深度测序，分别在 2 个月和 8 个月大时，代表疾病的前症状和症状阶段。我们的结果表明，与野生型对照组相比，在 2 个月和 8 个月大的 BACHD 小鼠中分别有 44 个和 26 个 miRNA 表达差异。过度表达分析表明，在 2 个月大的小鼠中上调的 miRNA 控制着 PI3K-Akt 和 mTOR 细胞信号通路中关键基因的表达。相反，在 2 个月大的 BACHD 小鼠中下调的 miRNA 调节与神经元疾病相关的基因。有趣的是，用靶向两个上调 miRNA（miR-449c-5p 和 miR-146b-5p）的反义 miR 处理的原代纹状体神经元表现出更高的细胞死亡水平。因此，我们的结果表明，在 2 个月大的 BACHD 小鼠中改变的 miRNA 调节参与促进细胞存活的基因。值得注意的是，在 8 个月大时，差异表达的 miRNA 的靶标在相同的途径中没有明显富集。总之，我们的数据阐明了 miRNA 在 HD 早期阶段的作用，表明了作为维持或重新建立细胞内稳态的尝试的神经保护作用。
