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.