Dysregulation of zebrin-II cell subtypes in the cerebellum is a shared feature across polyglutamine ataxia mouse models and patients.

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. Editor's summary: Spinocerebellar ataxias (SCAs) are neurodegenerative diseases affecting coordination and movement. Purkinje cells (PCs) are especially vulnerable in SCAs, but their low abundance makes cell type–specific transcriptomic profiling difficult. Using a PC enrichment protocol for snRNA-seq, Bartelt et al. discovered that genes contributing to zebrin-II PC subtype identity were dysregulated in the SCA7-266Q mouse model. Immunohistochemistry revealed a loss of zebrin-II striping in the cerebella of SCA7-266Q mice and mouse models of other SCA subtypes. snRNA-seq on postmortem cerebellar tissue from patients with SCA7 demonstrated zebrin-II dysregulation in molecular layer interneurons. These results suggest that dysregulation of zebrin-II cell subtypes in the cerebellum is a shared feature across SCAs. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]