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。MicroRNA (miRNA) 是非编码 RNA，参与基因表达的转录后调控和微调。几项研究确定了 HD 和其他神经退行性疾病中 miRNA 表达的改变，但是它们在 HD 早期阶段的作用仍然难以捉摸。在这里，我们对 2 个月和 8 个月大的 HD 小鼠模型 BACHD 纹状体的 miRNA 进行了深度测序，代表了疾病的症状前和症状阶段。我们的结果表明，与野生型对照相比，44 和 26 种 miRNA 分别在 2 个月和 8 个月大的 BACHD 小鼠中差异表达。过度表达分析表明，在 2 个月大的小鼠中上调的 miRNA 控制了对 PI3K-Akt 和 mTOR 细胞信号通路至关重要的基因的表达。相反，在 2 个月大的 BACHD 小鼠中，调节参与神经元疾病的基因的 miRNA 被下调。有趣的是，用靶向两种上调 miRNA miR-449c-5p 和 miR-146b-5p 的抗 miRs 处理的原代纹状体神经元显示出更高水平的细胞死亡。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，过度表达表明在 8 个月大时差异表达的 miRNA 的靶标没有显着富集相同的途径。总之，我们的数据阐明了 miRNA 在 HD 初始阶段的作用，