A Neural Basis for Mutant ATAXIN-1 Induced Respiratory Dysfunction in Mouse Models of Spinocerebellar Ataxia Type 1

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disorder caused by an expanded trinucleotide repeat in the ATAXIN-1 (ATXN1) gene. SCA1 is characterized by motor dysfunction, cognitive impairment, and death from compromised swallowing and respiration. To delineate specific cell types that contribute to respiratory dysfunction, I utilized a conditional knock-in mouse model of SCA1, f-ATXN1146Q/2Q mice. Whole body plethysmography during spontaneous respiration and a combined hypoxic and hypercapnic challenge showed that f-ATXN1146Q/2Q mice exhibit a spontaneous respiratory phenotype characterized by elevated respiratory output. Consequently, the ability of f-ATXN1146Q/2Q mice to increase ventilation during the challenge is impaired. To investigate the role of mutant ATXN1 expression in neural and skeletal muscle lineages, f-ATXN1146Q/2Q mice were bred to Nestin-Cre and Acta1-Cre mice respectively. These analyses revealed that the abnormal spontaneous respiration in f-ATXN1146Q/2Q mice involved a behavioral phenotype in which SCA1 mice exhibit increased motor activity and functional dysregulation of central respiratory control centers. Both aspects of respiratory dysfunction were ameliorated by removing mutant ATXN1 from neural, but not skeletal muscle, cell lineages. Analysis of Phox2b-Cre mice indicate a role for Phox2b derived respiratory populations in the dysfunction of central respiratory circuitry, but was not found to have an effect on behavioral dysregulation during spontaneous respiration. The findings from this project establish f-ATXN1146Q/2Q mice as a model to explore mechanisms of respiratory dysfunction and support findings in SCA1 patients that brainstem and spinal cord involvement is a critical aspect of breathing dysfunction.