Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1. Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1

Neurodegeneration is a protracted process involving progressive changes in myriad cell types that ultimately result in the death of vulnerable neuronal populations. To dissect how individual cell types within a heterogeneous tissue contribute to the pathogenesis and progression of a neurodegenerative disorder, we performed longitudinal single-nucleus RNA sequencing of mouse and human spinocerebellar ataxia type 1 (SCA1) cerebellar tissue, establishing continuous dynamic trajectories of each cell population. Importantly, we defined the precise transcriptional changes that precede loss of Purkinje cells and, for the first time, identified robust early transcriptional dysregulation in unipolar brush cells and oligodendroglia. Finally, we applied a deep learning method to predict disease state accurately and identified specific features that enable accurate distinction of wild-type and SCA1 cells. Together, this work reveals new roles for diverse cerebellar cell types in SCA1 and provides a generalizable analysis framework for studying neurodegeneration. Overall design: Single-nucleus RNA-sequencing was performed of control and SCA1 human post-mortem cerebellar cortex tissues and SCA1 knock-in (KI; Atxn1 154Q/2Q) and wild-type (WT) littermate control mice to examine the complex and dynamic interplay between diverse cell populations in the SCA1 cerebellum over time.

神经退行性变是一种漫长的病理过程，涉及多种细胞类型的进行性改变，最终导致易感神经元群体死亡。为解析异质性组织内的单个细胞类型如何参与神经退行性疾病的发病机制与疾病进展，本研究对小鼠及人类1型脊髓小脑共济失调（spinocerebellar ataxia type 1, SCA1）小脑组织开展了纵向单细胞核RNA测序，构建了各细胞群体的连续动态轨迹。值得注意的是，本研究明确了浦肯野细胞（Purkinje cell）丢失前的精准转录组改变，并首次在单极刷细胞（unipolar brush cell）与少突胶质细胞（oligodendroglia）中鉴定出显著的早期转录失调。最后，本研究应用深度学习方法实现了疾病状态的精准预测，并筛选出可精准区分野生型（wild-type, WT）与SCA1细胞的特异性特征。综上，本研究揭示了多种小脑细胞类型在SCA1发病过程中的新功能，并为神经退行性变的研究提供了可推广的分析框架。研究设计：本研究对对照及SCA1患者死后小脑皮层组织，以及SCA1敲入（knock-in, KI; Atxn1 154Q/2Q）小鼠与野生型（WT）同窝对照小鼠的样本进行单细胞核RNA测序，以解析SCA1小脑内多种细胞群体随时间推移的复杂动态相互作用。