What is it about?
Charcot-Marie-Tooth disease (CMT) is a peripheral nerve disorder caused by mutations in over 80 different genes. The 2D subtype (CMT2D) results from dominantly inherited, toxic, gain-of-function mutations in the widely expressed housekeeping gene, GARS. We have examined the development and degeneration of the neuromuscular junction (NMJ) in different muscles of two mouse models of CMT2D, showing that this synapse between motor neurons and muscles is an important site of early, selective pathology.
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Why is it important?
By examining and comparing both distal and proximal muscles in CMT2D mice, we show that muscles display differential susceptibility to GARS mutations, and that impaired NMJ development precedes loss of connectivity between lower motor nerves and muscle. This work links defects in NMJ maturation to loss in synapse connectivity, and identifies the NMJ as an early, but selective target of pathology in CMT2D.
Perspectives
NMJ degeneration is more prevalent in CMT2D muscles that show delayed synaptic development. We do not determine whether this impaired maturation is contributing to the demise of the NMJ or serving to counteract the denervation. By improving our understanding of this phenomenon, we may in the future be able to harness this knowledge to help preserve neuromuscular stability in the disease.
Dr James N Sleigh
University College London
Read the Original
This page is a summary of: Neuromuscular junction maturation defects precede impaired lower motor neuron connectivity in Charcot-Marie-Tooth type 2D mice, Human Molecular Genetics, December 2013, Oxford University Press (OUP),
DOI: 10.1093/hmg/ddt659.
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