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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE271392 | GEO | 2024/07/04

REPOSITORIES: GEO

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Project description:Comparative analysis of cerebellar gene expression changes occurring in Sca1154Q/2Q and Sca7266Q/5Q knock-in mice; Polyglutamine diseases are inherited neurodegenerative disorders caused by expansion of CAG repeats encoding a glutamine tract in the disease-causing proteins. There are nine disorders each having distinct features but also clinical and pathological similarities. In particular, spinocerebellar ataxia type 1 and type 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with degeneration of Purkinje cells. To determine whether the disorders share molecular pathogenic events, we studied two mouse models of SCA1 and SCA7 that express the glutamine-expanded protein from the respective endogenous loci. We found common transcriptional changes, with down-regulation of Insulin-like growth factor binding protein 5 (Igfbp5) representing one of the most robust changes. Igfbp5 down-regulation occurred in granule neurons through a non-cell autonomous mechanism and was concomitant with activation of of the Insulin-like growth factor (IGF) pathway and the type I IGF receptor on Purkinje cells. These data define one common pathogenic response in SCA1 and SCA7 and reveal the importance of intercellular mechanisms in their pathogenesis. Given that SCA1 and SCA7 share a cerebellar degenerative phenotype, we proposed that some shared molecular changes might occur in both diseases, and that common molecular alterations could pinpoint pathways that could be targeted to modulate or monitor the pathogenesis of more than one disease. We focused on transcriptional changes because both ATXN1 and ATXN7 play roles in transcriptional regulation and transcriptional defects can be detected in early-symptomatic stages of both SCA1 and SCA7 mouse models. To test our hypothesis, we examined cerebellar gene expression patterns in SCA1 and SCA7 knock-in (KI) models--Sca1154Q/2Q and Sca7266Q/5Q mice. Experiment Overall Design: Total cerebellar RNA samples were collected from Sca1154Q/2Q knock-in and wild type mice at the early symptomatic disease stage (4 weeks, n=3 knock-in and 3 wild type; 9-12 weeks, n=3 knock-in and 3 wild type). In parallel experiments, total cerebellar RNA samples were collected from Sca7266Q/5Q knock-in and wild type mice also at the early symptomatic disease stage (5 weeks, n=5 knock-in and 5 wild type).

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

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