Transcriptomic profiling of medulla and cervical spinal cord to study respiratory neuropathology in Spinocerebellar ataxia type 7

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurological disorder caused by a deleterious CAG repeat expansion in the coding region of the ataxin-7 gene. The number of CAG repeats determines the severity and age of onset of the disease. Infantile onset SCA7 leads to severe clinical manifestations including dysphagia, aspiration pneumonia and respiratory distress, but the exact cause of respiratory impairment remains unclear. Using the infantile SCA7 mouse model – the SCA7266Q/5Q mouse, we examined the impact of mutant ataxin-7 on the respiratory control centers. Specifically, we examined the effect of pathological poly-Q-ataxin-7 expression on hypoglossal (XII) and phrenic motor units. Further, we identified the transcript profile of the medulla and cervical spinal cord and, investigated the XII and phrenic nerve structure as well as the neuromuscular junctions in the diaphragm and tongue. SCA-7 astrocytes showed significant intranuclear and cytoplasmic inclusions of ataxin-7 in the XII and putative phrenic motor nuclei. Transcriptomic analysis revealed dysregulation of genes involved in amino acid and neurotransmitter transportation, and myelination. Additionally, SCA7 mice demonstrated blunted efferent output of the XII nerve and demyelination in both XII and phrenic nerves. Finally, there was an increased number of NMJ clusters with higher expression of synaptic markers in SCA7 mice compared to WT controls. Thus, pathological ataxin-7 expression disrupts myelination and neurotransmitter transportation, and impairs glial cell function in the respiratory control centers. These pre-clinical findings elucidate the underlying pathophysiology responsible for dysphagia, aspiration and respiratory failure in infantile SCA7.