Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias

Bartelt, L. C.; Switonski, P. M.; Carvalho, J.; Duvick, L. A.; Scoles, D. R.; Pulst, S. M.; Orr, H. T.; Hull, C.; Lowe, C. B.; La Spada, A. R.

doi:10.1101/2023.03.19.533345

bioRxiv · 10.1101/2023.03.19.533345

Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias

Bartelt, L. C.·Switonski, P. M.·Carvalho, J.·Duvick, L. A.·Scoles, D. R.·Pulst, S. M.·Orr, H. T.·Hull, C.·Lowe, C. B.·La Spada, A. R.

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Abstract

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. SCA7 patients display a striking loss of Purkinje cell (PC) neurons with disease progression; however, PCs are rare, making them difficult to characterize. We developed a PC nuclei enrichment protocol and applied it to single-nucleus RNA-seq of a SCA7 knock-in mouse model. Our results unify prior observations into a central mechanism of cell identity loss, impacting both glia and PCs, driving accumulation of inhibitory synapses and altered PC spiking. Zebrin-II subtype dysregulation is the predominant signal in PCs, leading to complete loss of zebrin-II striping at motor symptom onset in SCA7 mice. We show this zebrin-II subtype degradation is shared across Polyglutamine Ataxia mouse models and SCA7 patients. It has been speculated that PC subtype organization is critical for cerebellar function, and our results suggest that a breakdown of zebrin-II parasagittal striping is pathological.

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Bartelt, L. C., Switonski, P. M., Carvalho, J., Duvick, L. A., Scoles, D. R., Pulst, S. M., Orr, H. T., Hull, C., Lowe, C. B., La Spada, A. R.. 2023-03-20. Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias. https://doi.org/10.1101/2023.03.19.533345

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