Sleigh, JN;
Dawes, JM;
West, SJ;
Wei, N;
Spaulding, EL;
Gómez-Martín, A;
Zhang, Q;
... Schiavo, G; + view all
(2017)
Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations.
Proceedings of the National Academy of Sciences of the United States of America
, 114
(16)
E3324-E3333.
10.1073/pnas.1614557114.
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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 of 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 non-progressive, indicating that sensory neuron identity is pre-natally perturbed and that a critical developmental insult is key to the afferent pathology. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause mis-activation of Trk signalling, which is essential for sensory neuron differentiation and development. Together, this work suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments.
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