Respiratory neuropathology in spinocerebellar ataxia type 7

被引:0
|
作者
Biswas, Debolina D. [1 ]
Shi, Yihan [1 ]
El Haddad, Lea [1 ]
Sethi, Ronit [1 ]
Huston, Meredith [1 ]
Kehoe, Sean [1 ]
Scarrow, Evelyn R. [1 ]
Strickland, Laura M. [1 ]
Pucci, Logan A. [1 ]
Dhindsa, Justin S. [1 ]
Hunanyan, Ani [1 ]
La Spada, Albert R. [2 ,3 ,4 ,5 ,6 ]
ElMallah, Mai K. [1 ]
机构
[1] Duke Univ, Med Ctr, Dept Pediat, Div Pulm & Sleep Med, Box 2644, Durham, NC 27710 USA
[2] Univ Calif Irvine Irvine, Dept Pathol & Lab Med, Irvine, CA USA
[3] Univ Calif Irvine, Dept Neurol, Irvine, CA USA
[4] Univ Calif Irvine, Dept Biol Chem, Irvine, CA USA
[5] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA USA
[6] Univ Calif Irvine, UCI Ctr Neurotherapeut, Irvine, CA USA
关键词
POLYGLUTAMINE-EXPANDED ATAXIN-7; TUMOR-NECROSIS-FACTOR; LONG-TERM FACILITATION; PRE-BOTZINGER COMPLEX; MUTANT ATAXIN-7; GLYCINE TRANSPORTERS; EXPRESSION ANALYSIS; SPINAL-CORD; MOUSE MODEL; HUMAN BRAIN;
D O I
10.1172/jci.insight.170444
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 SCA7(266Q/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. SCA7(266Q/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, SCA7(266Q/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 SCA7(266Q/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.
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页数:17
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