4.7 Article

Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C

期刊

出版社

MDPI
DOI: 10.3390/ijms19124072

关键词

Charcot-Marie-Tooth disease 4C; SH3TC2; neuromuscular junction; mouse models; peripheral neuropathy; demyelination

资金

  1. French Muscular Dystrophy Association (AFM-Telethon) [21644]
  2. Ministerium fur Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen
  3. Senatsverwaltung fur Wirtschaft, Technologie und Forschung des Landes Berlin
  4. Bundesministerium fur Bildung und Forschung
  5. University of Bologna
  6. Wellcome Trust Pathfinder Award [201064/Z/16/Z]
  7. StratNeuro
  8. Swedish Research Council
  9. Medical research Council (UK) [MR/N025431/1]
  10. Wellcome Investigator fund [109915/Z/15/Z]
  11. MRC [MR/N025431/1, MR/N025431/2, MR/N010035/1, G1000848] Funding Source: UKRI

向作者/读者索取更多资源

The neuromuscular junction (NMJ) appears to be a site of pathology in a number of peripheral nerve diseases. Charcot-Marie-Tooth (CMT) 4C is an autosomal recessive, early onset, demyelinating neuropathy. Numerous mutations in the SH3TC2 gene have been shown to underlie the condition often associated with scoliosis, foot deformities, and reduced nerve conduction velocities. Mice with exon 1 of the Sh3tc2 gene knocked out demonstrate many of the features seen in patients. To determine if NMJ pathology is contributory to the pathomechanisms of CMT4C we examined NMJs in the gastrocnemius muscle of SH3TC2-deficient mice. In addition, we performed proteomic assessment of the sciatic nerve to identify protein factors contributing to the NMJ alterations and the survival of demyelinated axons. Morphological and gene expression analysis of NMJs revealed a lack of continuity between the pre- and post-synaptic apparatus, increases in post-synaptic fragmentation and dispersal, and an increase in expression of the gamma subunit of the acetylcholine receptor. There were no changes in axonal width or the number of axonal inputs to the NMJ. Proteome investigations of the sciatic nerve revealed altered expression of extracellular matrix proteins important for NMJ integrity. Together these observations suggest that CMT4C pathology includes a compromised NMJ even in the absence of changes to the innervating axon.

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