Phrenic and Hypoglossal motor unit pathology in a Spinocerebellar ataxia type 7 mouse model

Abstract

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by a deleterious CAG repeat expansion in the coding region of the ataxin-7 gene on chromosome 3. Patients with infantile SCA-7 have the largest repeat expansion (>200 repeats) and the most severe disease characterized by progressive loss of coordination, dysarthria, dysphagia and retinal degeneration. Death in these infants results from severe hypotonia, aspiration pneumonia and respiratory failure. To understand the mechanism behind aspiration and respiratory failure in SCA7, we comprehensively examined hypoglossal (XII) and phrenic neuropathology of a mouse model of infantile SCA7: the SCA7-266Q mice. Previously, we showed that SCA7-266Q mice exhibit progressive respiratory dysfunction along with irregular breathing and prolonged apneic events by 9-11 weeks of age. In this study, we performed post-mortem histological analysis of the XII and phrenic motor neurons and nerves in SCA-7 and WT control mice at 9 weeks of age. Specifically, we studied the presence of glial cells and the degree of neurodegeneration within these motor nuclei. We also performed g-ratio analysis on semi-thin sections of the XII and phrenic nerves. Finally, using electron microscopy, we examined the mitochondrial and myelin pathology in XII and phrenic nerves. The phrenic motor neurons exhibit enhanced neurodegeneration, exacerbated astrogliosis and microglial recruitment in the motor neuron pool. In addition, the XII and phrenic nerves of SCA7-266Q mice have increased g-ratio compared to WT controls which signifies thinning of myelin sheaths and is consistent with demyelination. Furthermore, EM images of the XII and phrenic nerves demonstrate an increase in size of mitochondria in SCA7-266Q mice compared to their WT controls. Finally, preliminary qPCR data exhibited an anomaly in the expression of the neuromuscular junction markers in the diaphragm of the SCA7-266Q mice. Clinically, these findings underscore the importance of respiratory neuropathology that is responsible for the dysphagia, aspiration pneumonia and respiratory failure seen in infantile SCA7.