Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations.

Autor:	Sleigh JN; Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom; j.sleigh@ucl.ac.uk giampietro.schiavo@ucl.ac.uk., Dawes JM; Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom., West SJ; Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom., Wei N; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037., Spaulding EL; The Jackson Laboratory, Bar Harbor, ME 04609.; Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME 04469., Gómez-Martín A; Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom., Zhang Q; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037., Burgess RW; The Jackson Laboratory, Bar Harbor, ME 04609.; Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME 04469., Cader MZ; Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom., Talbot K; Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom., Yang XL; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037., Bennett DL; Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom., Schiavo G; Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom; j.sleigh@ucl.ac.uk giampietro.schiavo@ucl.ac.uk.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Apr 18; Vol. 114 (16), pp. E3324-E3333. Date of Electronic Publication: 2017 Mar 28.
DOI:	10.1073/pnas.1614557114
Abstrakt:	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 behavior 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. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause misactivation of Trk signaling, 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. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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