Longitudinal Study and Characterization of Gait Impairment in a Mouse Model of SCA1.

Abstract

Spinocerebellar ataxia 1 (SCA1) is a rare autosomal dominant neurodegenerative disease characterized by impaired gait, coordination, and balance. SCA1 results from an expanded CAG repeat in the Atxn1 gene, inducing protein aggregation and ultimately leading to the degeneration of cerebellar Purkinje cells. Clinical studies have shown that gait impairments, such as changes in stride length (SL), stride time, and stance phase, are seen in patients with cerebellar diseases. The SCA1^154Q/2Q mouse model reflects the longitudinal progression of SCA1 in humans, displaying motor incoordination, muscle atrophy, and cerebellar Purkinje cell degradation. In this study, we aim to characterize the progression of gait impairments that arise in the SCA1^154Q/2Q mouse model. The DigiGait™ system, which utilizes ventral plane imaging technology, was used to track gait parameters in SCA^154Q/2Q mice, beginning at 7 weeks of age until 42 weeks. Our data revealed that SCA^154Q/2Q males exhibited decreasing gait speeds beginning weeks 15-16 (p < 0.05), and SCA^154Q/2Q females showed gait speed declining as early as 9 weeks (p < 0.05). A decrease in SL was also found; these emerged at different time points in SCA1^154Q/2Q mice, ranging from weeks 14 to 32. Our data also suggest that SCA1 mice have decreased loading speed in hindlimbs with lower MAX dA/dt values at weeks 30 and 40 in both males and females (p < 0.01). Our characterization of this model establishes a framework for sex- and age-related differences, as well as a timeline of various gait performance metrics, which provides a foundation to test the efficacy of novel therapeutics.