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

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...

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Autores principales: Cipriani, Silvia, Phan, Vietxuan, Médard, Jean-Jacques, Horvath, Rita, Lochmüller, Hanns, Chrast, Roman, Roos, Andreas, Spendiff, Sally
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320960/
https://www.ncbi.nlm.nih.gov/pubmed/30562927
http://dx.doi.org/10.3390/ijms19124072
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author Cipriani, Silvia
Phan, Vietxuan
Médard, Jean-Jacques
Horvath, Rita
Lochmüller, Hanns
Chrast, Roman
Roos, Andreas
Spendiff, Sally
author_facet Cipriani, Silvia
Phan, Vietxuan
Médard, Jean-Jacques
Horvath, Rita
Lochmüller, Hanns
Chrast, Roman
Roos, Andreas
Spendiff, Sally
author_sort Cipriani, Silvia
collection PubMed
description 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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spelling pubmed-63209602019-01-07 Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C Cipriani, Silvia Phan, Vietxuan Médard, Jean-Jacques Horvath, Rita Lochmüller, Hanns Chrast, Roman Roos, Andreas Spendiff, Sally Int J Mol Sci Article 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. MDPI 2018-12-17 /pmc/articles/PMC6320960/ /pubmed/30562927 http://dx.doi.org/10.3390/ijms19124072 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cipriani, Silvia
Phan, Vietxuan
Médard, Jean-Jacques
Horvath, Rita
Lochmüller, Hanns
Chrast, Roman
Roos, Andreas
Spendiff, Sally
Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C
title Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C
title_full Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C
title_fullStr Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C
title_full_unstemmed Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C
title_short Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C
title_sort neuromuscular junction changes in a mouse model of charcot-marie-tooth disease type 4c
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320960/
https://www.ncbi.nlm.nih.gov/pubmed/30562927
http://dx.doi.org/10.3390/ijms19124072
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