Neural basis for mutant ATAXIN-1 induced respiratory dysfunction in mouse models of spinocerebellar ataxia type 1.

Spinocerebellar ataxia type 1 is a neurodegenerative disease characterized by motor dysfunction and premature death usually from compromised swallowing and respiration. Using plethysmography, we characterized respiration in the conditional f-ATXN1146Q/2Q SCA1 model. We found a progressive elevation of baseline respiration that impairs ability of f-ATXN1146Q/2Q mice to increase breathing during challenge. To delineate regions contributing to respiratory dysfunction, f-ATXN1146Q/2Q mice were crossed with Nestin-Cre and Acta1-Cre mice, respectively. Respiration improved by removing mATXN1 from neural lineages, but not from skeletal muscle demonstrating mATXN1 in the central nervous system is a key driver of respiratory dysfunction in SCA1 mouse models. Moreover, respiratory dysfunction in SCA1 mice involves two aspects: behavioral dysregulation exhibited as increased movement during plethysmography, and functional dysregulation of respiratory circuitry. As both of these aspects are rescued by deleting mATXN1 from neural cells, we further investigated the role of cerebellar Purkinje cells and chemosensing neurons in the brain stem in SCA1 respiratory phenotype. Our results indicate complex multiregional etiology of respiratory dysfunction. Mechanistically we found that in contrast to most other SCA1 symptoms, nuclear localization of mATXN1 does not play a key role in respiratory dysfunction.