title: Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused byGarsmutations.
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,GARSThe 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 byGarsmutations, 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.
authors.affiliation: 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.
authors.forename: James N
authors.identifier: 0000-0002-3782-9045
authors.initials: JN
authors.lastname: Sleigh
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
authors.forename: John M
authors.initials: JM
authors.lastname: Dawes
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: West
authors.affiliation: Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Na
authors.initials: N
authors.lastname: Wei
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609.|Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME 04469.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Spaulding
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.
authors.forename: Adriana
authors.initials: A
authors.lastname: Gómez-Martín
authors.affiliation: Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609.|Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME 04469.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Burgess
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
authors.forename: M Zameel
authors.initials: MZ
authors.lastname: Cader
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
authors.forename: Kevin
authors.identifier: 0000-0001-5490-1697
authors.initials: K
authors.lastname: Talbot
authors.affiliation: Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
authors.forename: David L
authors.initials: DL
authors.lastname: Bennett
authors.affiliation: 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.
authors.forename: Giampietro
authors.identifier: 0000-0002-4319-8745
authors.initials: G
authors.lastname: Schiavo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006032:Glycine-tRNA Ligase / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D020917:Receptor, trkA; D006032:Glycine-tRNA Ligase
keywords: Charcot–Marie–Tooth disease; aminoacyl-tRNA synthetase; distal spinal muscular atrophy type V; neurodevelopment; neuromuscular disease