Abstract
Dominantly inherited, missense mutations in the widely expressed housekeeping gene, GARS1, cause Charcot-Marie-Tooth type 2D (CMT2D), a peripheral neuropathy characterised by muscle weakness and wasting in limb extremities. Mice modelling CMT2D display early and selective neuromuscular junction (NMJ) pathology, epitomised by disturbed maturation and neurotransmission, leading to denervation. Indeed, the NMJ disruption has been reported in several different muscles; however, a systematic comparison of neuromuscular synapses from distinct body locations has yet to be performed. We therefore analysed NMJ development and degeneration across five different wholemount muscles to identify key synaptic features contributing to the distinct pattern of neurodegeneration in CMT2D mice. Denervation was found to occur along a distal-to-proximal gradient, providing a cellular explanation for the greater weakness observed in mutant Gars hindlimbs compared with forelimbs. Nonetheless, muscles from similar locations and innervated by axons of equivalent length showed significant differences in neuropathology, suggestive of additional factors impacting on site-specific neuromuscular degeneration. Defective NMJ development preceded and associated with degeneration, but was not linked to a delay of wild-type NMJ maturation processes. Correlation analyses indicate that muscle fibre type nor synaptic architecture explain the differential denervation of CMT2D NMJs, rather it is the extent of post-natal synaptic growth that predisposes to neurodegeneration. Together, this work improves our understanding of the mechanisms driving synaptic vulnerability in CMT2D and hints at pertinent pathogenic pathways.
Highlights
Introduction CharcotMarie-Tooth disease (CMT) is an inherited peripheral neuropathy typified by degeneration of motor and sensory neurons, which triggers progressive muscle wasting and sensory deficits mainly in the feet and hands[1]
Mutant Gars mice display a developmental perturbation of sensory neuron fate in hindlimb-innervating lumbar dorsal root ganglia (DRG)[17], which is not present in forelimb-innervating cervical DRG35, suggestive of lengthdependent phenotypes in Charcot-MarieTooth type 2D (CMT2D) mice
We found that developing synapses show greater inter-muscle variability and that post-natal neuromuscular junction (NMJ) growth occurs at different rates across muscles32—two phenotypes that may provide a substrate for differential NMJ degeneration in CMT2D
Summary
Introduction CharcotMarie-Tooth disease (CMT) is an inherited peripheral neuropathy typified by degeneration of motor and sensory neurons, which triggers progressive muscle wasting and sensory deficits mainly in the feet and hands[1]. Lumbrical muscles involved in hindpaw clasping and grip strength, show a progressive loss of lower motor neuron connectivity in mutant Gars mice, correlating with overall model severity[28]. To test whether this link between perturbed NMJ maturation and degeneration is consistent across CMT2D muscles, we assessed synaptic development in hindpaw and forepaw lumbricals (Fig. 2).
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