Abstract
Charcot-Marie-Tooth (CMT) disease is an inherited peripheral motor and sensory neuropathy. The disease is divided into demyelinating (CMT1) and axonal (CMT2) neuropathies, and although we have gained molecular information into the details of CMT1 pathology, much less is known about CMT2. Due to its clinical and genetic heterogeneity, coupled with a lack of animal models, common underlying mechanisms remain elusive. In order to gain an understanding of the normal function of genes associated with CMT2, and to draw direct comparisons between them, we have studied the behavioural, cellular and molecular consequences of mutating nine different genes in the nematode Caenorhabditis elegans (lin-41/TRIM2, dyn-1/DNM2, unc-116/KIF5A, fzo-1/MFN2, osm-9/TRPV4, cua-1/ATP7A, hsp-25/HSPB1, hint-1/HINT1, nep-2/MME). We show that C. elegans defective for these genes display debilitated movement in crawling and swimming assays. Severe morphological defects in cholinergic motors neurons are also evident in two of the mutants (dyn-1 and unc-116). Furthermore, we establish methods for quantifying muscle morphology and use these to demonstrate that loss of muscle structure occurs in the majority of mutants studied. Finally, using electrophysiological recordings of neuromuscular junction (NMJ) activity, we uncover reductions in spontaneous postsynaptic current frequency in lin-41, dyn-1, unc-116 and fzo-1 mutants. By comparing the consequences of mutating numerous CMT2-related genes, this study reveals common deficits in muscle structure and function, as well as NMJ signalling when these genes are disrupted.
Highlights
First identified in 1886, Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with an estimated prevalence of 1 in 2,500 individuals [1, 2]
To expand our global understanding of the cellular roles for genes implicated in CMT2, instead of generating strains that carry individual patient-specific mutations, we have assessed the consequences of genetic recessive null or loss-of-function alleles
As defective locomotion is a major symptom in CMT2 patients, we first sought to test whether loss-of-function alleles in the orthologous genes in C. elegans would result in similar behavioural phenotypes
Summary
First identified in 1886, Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with an estimated prevalence of 1 in 2,500 individuals [1, 2]. Common clinical features of CMT include slowly progressive distal muscle weakness and atrophy, distal. Disruption of genes linked to CMT disease cause behavioural, cellular and molecular defects in C. elegans design, data collection and analysis, decision to publish, or preparation of the manuscript
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