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bioRxiv2021

Disrupting ATXN1 Nuclear Localization in a Knock-in SCA1 Mouse Model Improves a Spectrum of SCA1-Like Phenotypes and their Brain Region Associated Transcriptomic Profiles

Spinocerebellar ataxia type 1 (SCA1) is a dominant trinucleotide repeat neurodegenerative disease characterized by motor dysfunction, cognitive impairment, and premature death. Degeneration of cerebellar Purkinje cells is a frequent and prominent pathological feature of SCA1. We previously showed that transport of ATXN1 to Purkinje cell nuclei is required for pathology, where mutant ATXN1 alters transcription. To examine the role of ATXN1 nuclear localization broadly in SCA1-like disease pathogenesis, CRISPR-Cas9 was used to develop a mouse with the amino acid alteration (K772T) in the nuclear localization sequence of the expanded ATXN1 protein. Characterization of these mice indicates proper nuclear localization of mutant ATXN1 contributes to many disease-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality. RNA sequencing analysis of genes whose expression was corrected to WT levels in Atxn1175QK772T/2Q mice indicates that transcriptomic aspects of SCA1 pathogenesis differ between the cerebellum, brainstem, cerebral cortex, hippocampus, and striatum.

neuroscience↗

bioRxiv2021

Early stage of Spinocerebellar Ataxia Type 1 (SCA1) progression exhibits region- and cell-specific pathology and is partially ameliorated by Brain Derived Neurotrophic Factor (BDNF)

While astrocyte heterogeneity is an important feature of the healthy brain, less is understood about spatiotemporal heterogeneity of astrocytes in brain disease. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a CAG repeat expansion mutation in the gene Ataxin1 (ATXN1). We characterized astrocytes across disease progression in the four clinically relevant brain regions, cerebellum, brainstem, hippocampus, and motor cortex of Atxn1154Q/2Q mice, a knock-in mouse model of SCA1. We found brain region specific changes in astrocyte density, GFAP expression and area, early in disease and prior to neuronal loss. Expression of astrocytic core homeostatic genes was also altered in a brain-region specific manner and correlated with neuronal activity indicating that astrocytes may compensate or exacerbate neuronal dysfunction in a brain region specific manner. Late in disease, expression of astrocytic homeostatic genes was reduced in all four brain regions indicating loss of astrocyte functions. We observed spatiotemporal changes in microglia with no obvious correlation with spatiotemporal astrocyte alterations indicating a complex orchestration of glial phenotypes in disease. These results support spatiotemporal diversity of glial phenotypes as an important feature of the brain disease that may contribute to SCA1 pathogenesis in a brain-region and disease stage-specific manner.

neuroscience↗