Sensory neuron fate is developmentally perturbed byGarsmutations causing human neuropathy

Abstract

Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS. The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system in CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by Gars mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in sensory behaviour concordant with the afferent imbalance, which is present at birth and nonprogressive, indicating that sensory neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. This suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments. Significance StatementCharcot-Marie-Tooth disease (CMT) is a collection of genetically diverse inherited nerve disorders with the unifying feature of peripheral neuron degeneration. The mechanisms triggering this motor and sensory nerve dysfunction remain unresolved, as does the reason for the lack of sensory pathology observed in distal hereditary motor neuropathies, which can be associated with CMT genes. To unravel the mechanisms leading to afferent deterioration, we have studied the sensory nervous system of CMT Type 2D mice. Our work indicates that the specific cellular identity of sensory nerves is perturbed in mutant mice pre-natally. CMT therefore manifests through the complex interplay between malfunctioning developmental, maturation, and survival programs, which has important ramifications for therapeutic timing.Keywords: aminoacyl-tRNA synthetase (ARS), Charcot-Marie-Tooth disease (CMT), CMT2D, distal spinal muscular atrophy type V (dSMA-V), dorsal root ganglion (DRG), GARS, glycyl-tRNA synthetase (GlyRS), hereditary motor and sensory neuropathy (HMSN), muscle spindle, neurodevelopment, neuromuscular disease, peripheral neuropathy.

Compartmentalized Signaling in Neurons: From Cell Biology to Neuroscience

“…Additional analyses of other tRNA synthetase disease-causing mutants in Drosophila or in mouse models lead to similar conclusions that the disease is not due to a loss of the canonical function of these enzymes (Ermanoska et al, 2014;Storkebaum et al, 2009;Stum et al, 2011). On the contrary, recent studies have shown that tRNA synthetase mutations strikingly lead to toxic gains of function, impairing the signaling of different neurotrophic factor receptor families in the nervous system (He et al, 2015;Sleigh et al, 2017aSleigh et al, , 2017bStum et al, 2011). Thus, a class of diseases thought to be caused by impaired local translation in compartmentalized signaling is actually caused by the perturbation of another compartmentalized signaling mechanism orchestrated by neurotrophic factors.…”