Spinocerebellar ataxia type 7 (SCA7) is a genetic neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. Purkinje cells (PCs) are central to the pathology of ataxias, but their low abundance in the cerebellum underrepresents their transcriptomes in sequencing assays. To address this issue, we developed a PC enrichment protocol and sequenced individual nuclei from mice and patients with SCA7. Single-nucleus RNA sequencing in SCA7-266Q mice revealed dysregulation of cell identity genes affecting glia and PCs. Specifically, genes marking zebrin-II PC subtypes accounted for the highest proportion of DEGs in symptomatic SCA7-266Q mice. These transcriptomic changes in SCA7-266Q mice were associated with increased numbers of inhibitory synapses as quantified by immunohistochemistry and reduced spiking of PCs in acute brain slices. Dysregulation of zebrin-II cell subtypes was the predominant signal in PCs of SCA7-266Q mice and was associated with the loss of zebrin-II striping in the cerebellum at motor symptom onset. We furthermore demonstrated zebrin-II stripe degradation in additional mouse models of polyglutamine ataxia and observed decreased zebrin-II expression in the cerebella of patients with SCA7. Our results suggest that a breakdown of zebrin subtype regulation is a shared pathological feature of polyglutamine ataxias.

中文翻译：

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小脑中 zebrin-II 细胞亚型的失调是聚谷氨酰胺共济失调小鼠模型和患者的共同特征


脊髓小脑性共济失调 7 型 （SCA7） 是一种由 CAG-聚谷氨酰胺重复扩增引起的遗传性神经退行性疾病。浦肯野细胞 （PC） 是共济失调病理学的核心，但它们在小脑中的低丰度在测序分析中低含量不足。为了解决这个问题，我们开发了一种 PC 富集方案，并对小鼠和 SCA7 患者的单个细胞核进行了测序。SCA7-266Q 小鼠的单核 RNA 测序揭示了影响神经胶质细胞和 PC 的细胞身份基因失调。具体而言，标记 zebrin-II PC 亚型的基因在有症状的 SCA7-266Q 小鼠中占 DEGs 的最高比例。SCA7-266Q 小鼠的这些转录组变化与免疫组化定量的抑制性突触数量增加和急性脑切片中 PCs 尖峰的减少有关。zebrin-II 细胞亚型失调是 SCA7-266Q 小鼠 PC 中的主要信号，与运动症状发作时小脑中 zebrin-II 条纹的缺失有关。我们进一步在聚谷氨酰胺共济失调的其他小鼠模型中证明了 zebrin-II 条纹降解，并观察到 SCA7 患者小脑中 zebrin-II 表达降低。我们的结果表明，斑点蛋白亚型调控的崩溃是聚谷氨酰胺共济失调的共同病理特征。