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

Abstract

SUMMARYSpinocerebellar 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.

Delineating regional vulnerability in the neurodegenerative disease SCA1 using a conditional mutant ATXN1 mouse

“…Notably, deletion of f-ATXN1 146Q from muscle substantially reduced kyphosis that in mice is associated with paraspinal skeletal muscle atrophy 18 as well as restored normal dorsiflexor strength, muscle mass and fiber size. As seen for other SCA1-like phenotypes, motor dysfunction, cognitive deficits, and premature lethality 20 , proper nuclear localization of expanded ATXN1 was shown to be critical for muscle pathogenesis. These results show that f-ATXN1 146Q/2Q along with f-ATXN1 146Q/2Q ; Acta1-Cre will provide an excellent experimental platform for elucidating the molecular aspects of ATXN1[146Q]-induced muscle pathogenesis.…”

“…Recently, we found that proper nuclear localization of mutant ATXN1 is critical for many disease-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality 20 . Like f-ATXN1 146Q/2Q mice, we observed smaller dorsiflexor muscle mass (Fig.…”