Respiratory dysfunction in a mouse model of spinocerebellar ataxia type 7

Abstract

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the coding region of the ataxin-7 gene. Infantile-onset SCA7 patients display extremely large repeat expansions (>200 CAGs) and exhibit progressive ataxia, dysarthria, dysphagia and retinal degeneration. Severe hypotonia, aspiration pneumonia and respiratory failure often contribute to death in affected infants. To better understand the features of respiratory and upper airway dysfunction in SCA7, we examined breathing and putative phrenic and hypoglossal neuropathology in a knock-in mouse model of early-onset SCA7 carrying an expanded allele with 266 CAG repeats. Whole-body plethysmography was used to measure awake, spontaneous breathing at baseline in normoxia and during a hypercapnic/hypoxic respiratory challenge at 4 and 8 weeks, before and after onset of disease. Postmortem studies included quantification of putative phrenic and hypoglossal motor neurons and microglia and analysis of ataxin-7 aggregation at end stage. SCA7-266Q mice have profound breathing deficits during a respiratory challenge, exhibiting reduced respiratory output and a greater percentage of time in apnea. Histologically, putative phrenic and hypoglossal motor neurons of SCA7 mice exhibit a reduction in number accompanied by increased microglial activation, indicating neurodegeneration and neuroinflammation. Furthermore, intranuclear ataxin-7 accumulation is observed in cells neighboring putative phrenic and hypoglossal motor neurons in SCA7 mice. These findings reveal the importance of phrenic and hypoglossal motor neuron pathology associated with respiratory failure and upper airway dysfunction, which are observed in infantile-onset SCA7 patients and likely contribute to their early death.

The Molecular Basis of Spinocerebellar Ataxia Type 7

“…Respiratory failure is reported frequently in infantile SCA7. To get a better understanding of respiratory failure pathogenesis, the putative phrenic and hypoglossal neuropathology in a SCA7-266Q knock-in mouse was examined ( Fusco et al, 2021 ). The SCA7-266 knock-in mice showed difficulty in breathing during a respiratory challenge along with a reduction in the respiratory output.…”

“…SCA7-266Q knock-in mice also showed accumulation of intranuclear ataxin-7 around the putative phrenic and hypoglossal motor neurons. This loss of neuronal cells may explain symptoms associated with respiratory deficit such as decreased respiratory capacity and minute ventilation due to insufficient control of these two nerves on breathing muscles ( Fusco et al, 2021 ).…”

“…Potential mechanisms for the others may involve coordinating TBP and ATXN7 at the promoters of genes related to metabolic activity and the hypothalamic-pituitary-adrenal axis ( Gardiner et al, 2019 ). Determining how these proteins intersect to regulate gene expression or perhaps a role in mitochondrial regulation (see above – SCA7 as a mitochondrial disease) may help isolate pathways relevant to BMI ( Fusco et al, 2021 ). Overall, the role of “normal range” trinucleotide repeat size variations in ATXN7 , as well as those in other polyglutamine disease associated genes, requires further study.…”