Bioinformatic facility, Department of Cellular, Computational and Integrative Biology, CIBIO, University of Trento, Trento, Italy.
Biomedical Sciences and Biotechnology, University of Udine, Udine, Italy.
PLoS Genet. 2023 Oct 13;19(10):e1010988. doi: 10.1371/journal.pgen.1010988. eCollection 2023 Oct.
Alternative splicing (AS) appears to be altered in Huntington's disease (HD), but its significance for early, pre-symptomatic disease stages has not been inspected. Here, taking advantage of Htt CAG knock-in mouse in vitro and in vivo models, we demonstrate a correlation between Htt CAG repeat length and increased aberrant linear AS, specifically affecting neural progenitors and, in vivo, the striatum prior to overt behavioral phenotypes stages. Remarkably, a significant proportion (36%) of the aberrantly spliced isoforms are not-functional and meant to non-sense mediated decay (NMD). The expanded Htt CAG repeats further reflect on a previously neglected, global impairment of back-splicing, leading to decreased circular RNAs production in neural progenitors. Integrative transcriptomic analyses unveil a network of transcriptionally altered micro-RNAs and RNA-binding proteins (Celf, hnRNPs, Ptbp, Srsf, Upf1, Ythd2) which might influence the AS machinery, primarily in neural cells. We suggest that this unbalanced expression of linear and circular RNAs might alter neural fitness, contributing to HD pathogenesis.
选择性剪接 (AS) 在亨廷顿病 (HD) 中似乎发生了改变，但它对早期、无症状疾病阶段的意义尚未被检查。在这里，我们利用 Htt CAG 敲入小鼠的体外和体内模型，证明了 Htt CAG 重复长度与增加的异常线性 AS 之间存在相关性，特别是在明显的行为表型阶段之前，影响神经祖细胞，并且在体内影响纹状体。值得注意的是，相当一部分（36%）异常剪接的异构体是无功能的，意味着非意义介导的衰变（NMD）。扩展的 Htt CAG 重复进一步反映了以前被忽视的全球反式剪接受损，导致神经祖细胞中环状 RNA 产量减少。综合转录组分析揭示了一个转录改变的 micro-RNAs 和 RNA 结合蛋白（Celf、hnRNPs、Ptbp、Srsf、Upf1、Ythd2）的网络，这些可能影响 AS 机制，主要在神经细胞中。我们认为，这种线性和环状 RNA 的不平衡表达可能会改变神经适应性，导致 HD 的发病机制。
