Better understanding of the earliest molecular pathologies of all neurodegenerative diseases is expected to improve human therapeutics. We investigated the earliest molecular pathology of spinocerebellar ataxia type 1 (SCA1), a rare familial neurodegenerative disease that primarily induces death and dysfunction of cerebellum Purkinje cells. Extensive prior studies have identified involvement of transcription or RNA-splicing factors in the molecular pathology of SCA1. However, the regulatory network of SCA1 pathology, especially central regulators of the earliest developmental stages and inflammatory events, remains incompletely understood. Here, we elucidated the earliest developmental pathology of SCA1 using originally developed dynamic molecular network analyses of sequentially acquired RNA-seq data during differentiation of SCA1 patient-derived induced pluripotent stem cells (iPSCs) to Purkinje cells. Dynamic molecular network analysis implicated histone genes and cytokine-relevant immune response genes at the earliest stages of development, and revealed relevance of ISG15 to the following degradation and accumulation of mutant ataxin-1 in Purkinje cells of SCA1 model mice and human patients.

更好地了解所有神经退行性疾病的最早分子病理学有望改善人类治疗。我们研究了 1 型脊髓小脑共济失调 (SCA1) 的最早分子病理学，这是一种罕见的家族性神经退行性疾病，主要诱导小脑浦肯野细胞死亡和功能障碍。先前的大量研究已确定转录或 RNA 剪接因子参与 SCA1 的分子病理学。然而，SCA1 病理学的调控网络，尤其是最早发育阶段和炎症事件的中枢调控因子，仍不完全清楚。在这里，我们利用最初开发的动态分子网络分析，对 SCA1 患者来源的诱导多能干细胞 (iPSC) 分化为浦肯野细胞期间连续获取的 RNA-seq 数据，阐明了 SCA1 最早的发育病理学。动态分子网络分析表明组蛋白基因和细胞因子相关免疫应答基因处于发育的最早阶段，并揭示了ISG15与SCA1模型小鼠和人类患者浦肯野细胞中突变atataxin-1随后降解和积累的相关性。