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Disruption of genes associated with Charcot-Marie-Tooth type 2 lead to common behavioural, cellular and molecular defects in Caenorhabditis elegans

Ming S. Soh, Xinran Cheng, Jie Liu, Brent Neumann
doi: https://doi.org/10.1101/605584
Ming S. Soh
1Neuroscience Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne VIC 3800, Australia
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Xinran Cheng
1Neuroscience Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne VIC 3800, Australia
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Jie Liu
1Neuroscience Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne VIC 3800, Australia
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Brent Neumann
1Neuroscience Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne VIC 3800, Australia
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  • For correspondence: brent.neumann@monash.edu
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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 understand the biological importance of CMT2-casuative genes, we have studied the behavioural, cellular and molecular consequences of mutating nine different genes associated with CMT2 in the nematode Caenorhabditis elegans (lin-41/TRIM2, dyn-1/DMN2, 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 novel methods for quantifying muscle morphology and use these to demonstrate striking loss of muscle structure across the mutants that correspond with reductions in muscle function. 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.

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Posted April 11, 2019.
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Disruption of genes associated with Charcot-Marie-Tooth type 2 lead to common behavioural, cellular and molecular defects in Caenorhabditis elegans
Ming S. Soh, Xinran Cheng, Jie Liu, Brent Neumann
bioRxiv 605584; doi: https://doi.org/10.1101/605584
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Disruption of genes associated with Charcot-Marie-Tooth type 2 lead to common behavioural, cellular and molecular defects in Caenorhabditis elegans
Ming S. Soh, Xinran Cheng, Jie Liu, Brent Neumann
bioRxiv 605584; doi: https://doi.org/10.1101/605584

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