Respiratory neuropathology in spinocerebellar ataxia type 7
Debolina D. Biswas, Yihan Shi, Léa El Haddad, Ronit Sethi, Meredith Huston, Sean Kehoe, Evelyn R. Scarrow, Laura M. Strickland, Logan A. Pucci, Justin S. Dhindsa, Ani Hunanyan, Albert R. La Spada, Mai K. ElMallah
Debolina D. Biswas, Yihan Shi, Léa El Haddad, Ronit Sethi, Meredith Huston, Sean Kehoe, Evelyn R. Scarrow, Laura M. Strickland, Logan A. Pucci, Justin S. Dhindsa, Ani Hunanyan, Albert R. La Spada, Mai K. ElMallah
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Research Article Neuroscience Pulmonology

Respiratory neuropathology in spinocerebellar ataxia type 7

Abstract

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurological disorder caused by deleterious CAG repeat expansion in the coding region of the ataxin 7 gene (polyQ-ataxin-7). Infantile-onset SCA7 leads to severe clinical manifestation of 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 pathological polyQ-ataxin-7 on hypoglossal (XII) and phrenic motor units. We identified the transcript profile of the medulla and cervical spinal cord and investigated the XII and phrenic nerves and the neuromuscular junctions in the diaphragm and tongue. SCA7266Q/5Q astrocytes showed significant intranuclear inclusions of ataxin-7 in the XII and putative phrenic motor nuclei. Transcriptomic analysis revealed dysregulation of genes involved in amino acid and neurotransmitter transport and myelination. Additionally, SCA7266Q/5Q mice demonstrated blunted efferent output of the XII nerve and demyelination in both XII and phrenic nerves. Finally, there was an increased number of neuromuscular junction clusters with higher expression of synaptic markers in SCA7266Q/5Q mice compared with WT controls. These preclinical findings elucidate the underlying pathophysiology responsible for impaired glial cell function and death leading to dysphagia, aspiration, and respiratory failure in infantile SCA7.

Authors

Debolina D. Biswas, Yihan Shi, Léa El Haddad, Ronit Sethi, Meredith Huston, Sean Kehoe, Evelyn R. Scarrow, Laura M. Strickland, Logan A. Pucci, Justin S. Dhindsa, Ani Hunanyan, Albert R. La Spada, Mai K. ElMallah

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Figure 4

SCA7 mice exhibit significant XII and phrenic nerve pathology.

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SCA7 mice exhibit significant XII and phrenic nerve pathology. (A and B)...
(A and B) Representative bright-field images of 9-week WT (n = 4) and SCA7 (n = 4) toluidine blue–stained XII (A) and phrenic (B) nerves. Scale bars: 30 μm. (C and D) Graphical representation of g-ratio, myelin thickness, axon area, and total axon area with myelin sheath of XII nerve (C) in 9-week WT (n = 5) and SCA7 (n = 7) mice and phrenic nerve (D) in 9-week WT (n = 6) and SCA7 (n = 7) mice. (E and F) Expression of Plp1 by qPCR in the medulla (E) and cervical spinal cord (F) of 9-week WT (n = 4) and SCA7 (n = 4) mice. (G and H) Transmission electron microscopy images of XII (G) and phrenic (H) nerves from 9-week WT (n = 4) and SCA7 (n = 4) mice. Yellow arrows indicate demyelination, red arrows indicate decompaction of the myelin sheath, yellow asterisks indicate smaller sized axons, and red asterisks indicate accumulation of vacuoles in the axons and Schwann cells surrounding the axons. Scale bars: 2 μm. (I) Heatmap highlights differentially expressed genes regulating myelin sheath activity pathway in 9-week WT (n = 5) and SCA7 (n = 5) medulla and cervical spinal cord (C3–C5 region of the spinal cord). (J–O) Representative traces of WT (J–L) and SCA7 (M–O) XII nerve recordings at baseline (50% O2, 50% N2) and during a respiratory challenge (7% CO2, 21% O2/N2 balance). Expanded time-scale traces of the 10-second recording are shown for baseline (K and N) and challenge (L and O). (P) Graphical representation of XII nerve amplitude at baseline. The graph represents percentage of baseline for the amplitude of XII nerve amplitude of WT (n = 4) and SCA7 (n = 5) mice. Percentage of baseline was calculated as (challenge – baseline)/baseline × 100. (Q) Graphical representation of the frequency of XII nerve burst at baseline of WT (n = 4)and SCA7 (n = 5) mice. Data presented as mean ± SEM. **P < 0.01, ***P < 0.001, ****P < 0.0001 by 2-tailed Student’s t test.