ABSTRACT
Spinocerebellar ataxia type 7 (SCA7) is a dominantly inherited neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion in the ataxin-7 gene. SCA7 patients display retinal degeneration and cerebellar degeneration with a striking loss of Purkinje cell neurons as the disease progresses. The normal function of the ataxin-7 protein is closely tied to transcriptional regulation, as ataxin-7 is a core component of the STAGA co-activator complex. Using a genetic SCA7 knock-in mouse model, we profiled the gene expression signatures associated with SCA7 neurodegeneration at single-cell resolution, employing a novel Purkinje cell-enrichment method, followed by single-nucleus RNA-seq. We identified altered expression of inhibitory synapse genes, which upon detailed analysis of SCA7 transcriptome changes stemmed from dramatic dysregulation of Purkinje Cell zebrin-II (aldolase-C) subtypes. Indeed, zebrin-II gene regulatory networks were significantly impacted in presymptomatic mice, resulting in an obliteration of zebrin-II parasagittal striping at symptomatic stages. We also detected dysregulation of zebrin-II gene modules in human SCA7 patient cerebellum, accompanied by blunted zebrin-II expression. When we profiled cerebellar zebrin-II regulation in other SCA polyglutamine disease mouse models, we similarly observed a disintegration of zebrin-II striping in symptomatic animals, indicating that zebrin-II identity dysregulation could be a general mechanism of polyglutamine-driven ataxia. We then documented increased inhibitory synapses in SCA7 cerebellum, and detected slower spontaneous spiking frequencies and altered inhibitory postsynaptic currents in cerebellar slices from SCA7 mice, confirming the functional significance of this pathological synapse reorganization.
Competing Interest Statement
The authors have declared no competing interest.
