Disrupting Nuclear Localization of Expanded ATXN1 Mitigates SCA1 Phenotypes and Transcriptomic Perturbations Across Brain Regions

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a dominant neurodegenerative disease caused by ATAXIN1 (ATXN1) trinucleotide repeat expansion and characterized by motor dysfunction, cognitive impairment, and premature death. Degeneration of cerebellar Purkinje cells is a frequent and prominent pathological feature of SCA1. Previous research found that transport of ATXN1 to Purkinje cell nuclei is required for pathology, where mutant ATXN1 alters transcription. In addition to cerebellar degeneration, cell loss and atrophy has been observed in the medulla, cerebral cortex, hippocampus, and striatum of patients with SCA1. These brain regions have not historically been a major focus of SCA1 research. To test the hypothesis that nuclear localization of ATXN1 has a critical role in pathogenesis across diverse regions of the central nervous associated with SCA1, CRISPR-Cas9 was used to develop a knock-in SCA1 mouse model with an amino acid alteration (K772T) in the nuclear localization sequence of the expanded ATXN1 protein. Characterization of these Atxn1175QK772T/2Q mice indicates that nuclear localization of expanded ATXN1 contributes to many SCA1-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality. The K772T mutation reduces nuclear localization, improves extractability, and delays nuclear inclusion formation of expanded ATXN1 throughout the brain. RNA sequencing analyses show that transcriptomic aspects of SCA1 pathogenesis differ between the cerebellum, medulla, cerebral cortex, hippocampus, and striatum. The findings from this project establish that nuclear localization of expanded ATXN1 is a key aspect of SCA1 pathogenesis throughout the brain and suggest that the specific molecular mechanisms of disease progression are largely unique to each of the various brain regions affected.