Transcriptional dysregulation in the spinal cord of SCA3 provides insights into disease mechanisms [KO_RNAseq]

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by polyglutamine repeat expansion in the ATXN3 gene. Despite the ubiquitous expression of ATXN3 throughout the body, SCA3 pathology is pronounced in select, vulnerable regions within the central nervous system (CNS). Notably, imaging studies of SCA3 patients have revealed spinal cord atrophy prior to ataxia symptom onset and progressing with disease severity. However, the molecular mechanisms underlying SCA3 pathology in the spinal cord remain largely unexplored. Here, we present, for the first time, a comprehensive analysis of the spinal cord transcriptome using SCA3 tissue from humans and mouse models. Our data demonstrates both early and progressive transcriptional dysregulation in the spinal cord, impacting key biological processes such as lipid metabolism, inflammation, cellular structure, and nucleic acid processing. Transcriptomic profiling of Atxn3 knockout mice revealed only weak transcriptional changes in the spinal cord, with minimal overlap compared to the robust alterations observed in SCA3 knock-in mice, indicating that the molecular signature of the disease in the spinal cord is likely not driven by ATXN3 loss of function. In addition, we identified aberrant RNA splicing, particularly affecting genes involved in cytoskeletal organization. Collectively, our findings indicate that SCA3-associated transcriptional dysregulation in the spinal cord contributes to canonical pathological mechanisms of SCA3 both early and progressively. These results underscore the central role of the spinal cord in SCA3 pathogenesis and advocate for its inclusion as a key therapeutic target. Overall design: RNAseq of RNA collected from the spinal cord of Atxn3 KO and WT mice at 24 weeks of age.

3型脊髓小脑共济失调（Spinocerebellar ataxia type 3, SCA3）是一种由ATXN3基因内多聚谷氨酰胺重复扩增引发的神经退行性疾病。尽管ATXN3在全身广泛表达，但SCA3的病理改变主要集中在中枢神经系统（central nervous system, CNS）内特定的易感区域。值得注意的是，针对SCA3患者的影像学研究显示，脊髓萎缩可在共济失调症状发作前出现，并随疾病严重程度逐渐进展。然而，脊髓中SCA3病理的分子机制仍在很大程度上未被阐明。本研究首次对来自人类患者和小鼠模型的SCA3脊髓组织开展了全面的转录组分析。我们的研究数据表明，脊髓内存在早期且进行性的转录失调，可影响脂质代谢、炎症反应、细胞结构及核酸加工等关键生物学过程。对Atxn3敲除（Atxn3 knockout, KO）小鼠的转录组分析显示，其脊髓内仅出现微弱的转录变化，与SCA3敲入（knock-in, KI）小鼠中观察到的显著转录改变仅有极少重叠，这提示脊髓中疾病的分子特征并非由ATXN3功能丧失所驱动。此外，本研究还发现了异常的RNA剪接事件，尤其影响参与细胞骨架组织的相关基因。综上，我们的研究结果表明，脊髓中与SCA3相关的转录失调在疾病早期及进展阶段均参与了SCA3的典型病理机制。上述研究结果强调了脊髓在SCA3发病机制中的核心作用，并支持将其作为关键治疗靶点。整体实验设计：对24周龄的Atxn3敲除（KO）及野生型（wild type, WT）小鼠的脊髓组织提取RNA，进行RNA测序（RNAseq）。