Widespread dysregulation of mRNA splicing implicates RNA processing in the development and progression of Huntington’s disease

In Huntington’s disease (HD), a CAG repeat expansion mutation in the HTT gene drives a gain-of-function toxicity that disrupts mRNA processing. Although widespread dysregulation of gene splicing has been shown in human HD post-mortem brain tissue, post-mortem analyses are likely confounded by cell type composition changes in late stage HD, limiting the ability to identify dysregulation related to early pathogenesis. To study alternative splicing changes in early HD, we performed RNAsequencing analyses in an established isogenic HD neuronal cell model. We report cell type-associated and CAG length-dependent splicing changes, and find an enrichment of RNA processing genes coupled with neuronal function-related genes showing mutant HTT associated splicing. Comparisons with post-mortem data also identified splicing events associated with early pathogenesis that persist to later stages of disease, particularly in the striatum. Here, our results highlight splicing dysregulation in RNA processing genes in HD, leading to potential disrupted neuronal function and neuropathology.亨廷顿舞蹈症（Huntington’s disease, HD）中，HTT基因的CAG重复扩增突变可驱动功能获得性毒性，破坏mRNA加工过程。既往研究已证实，人类亨廷顿舞蹈症死后脑组织中存在广泛的基因剪接失调，但这类死后分析很可能因晚期疾病的细胞类型组成变化而受到混杂，进而限制了我们识别与早期发病机制相关的失调事件的能力。为探究亨廷顿舞蹈症早期的可变剪接变化，我们在已建立的同基因背景亨廷顿舞蹈症神经元细胞模型中开展了RNA测序分析。本研究报道了与细胞类型相关、且依赖CAG长度的剪接变化，并发现与突变型HTT相关的剪接事件在RNA加工基因与神经元功能相关基因中存在富集。通过与死后脑组织数据的对比，我们还鉴定出与早期发病机制相关的剪接事件，这类事件可持续存在至疾病晚期，尤以纹状体中表现显著。本研究结果揭示了亨廷顿舞蹈症中RNA加工基因的剪接失调，该失调可能引发神经元功能受损与神经病理改变。