4.6 Article

Altered Sensory Neuron Development in CMT2D Mice Is Site-Specific and Linked to Increased GlyRS Levels

期刊

FRONTIERS IN CELLULAR NEUROSCIENCE
卷 14, 期 -, 页码 -

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fncel.2020.00232

关键词

aminoacyl-tRNA synthetase (ARS); amyotrophic lateral sclerosis (ALS); axonal transport; Charcot-Marie-Tooth disease (CMT); glycyl-tRNA synthetase (GlyRS); neurotrophin receptors (Trks); sensory neuron; signaling endosome

资金

  1. Medical Research Council Career Development Award [MR/S006990/1]
  2. Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship [103191/Z/13/Z]
  3. Wellcome Trust Senior Investigator Award [107116/Z/15/Z]
  4. European Union's Horizon 2020 Research and Innovation Programme [739572]
  5. UK Dementia Research Institute Foundation [UKDRI-1005]
  6. Wellcome Trust [103191/Z/13/Z, 107116/Z/15/Z] Funding Source: Wellcome Trust
  7. MRC [MR/S006990/1] Funding Source: UKRI

向作者/读者索取更多资源

Dominant, missense mutations in the widely and constitutively expressedGARS1gene cause peripheral neuropathy that usually begins in adolescence and principally impacts the upper limbs. Caused by a toxic gain-of-function in the encoded glycyl-tRNA synthetase (GlyRS) enzyme, the neuropathology appears to be independent of the canonical role of GlyRS in aminoacylation. Patients display progressive, life-long weakness and wasting of muscles in hands followed by feet, with frequently associated deficits in sensation. When dysfunction is observed in motor and sensory nerves, there is a diagnosis of Charcot-Marie-Tooth disease type 2D (CMT2D), or distal hereditary motor neuropathy type V if the symptoms are purely motor. The cause of this varied sensory involvement remains unresolved, as are the pathomechanisms underlying the selective neurodegeneration characteristic of the disease. We have previously identified in CMT2D mice that neuropathy-causingGarsmutations perturb sensory neuron fate and permit mutant GlyRS to aberrantly interact with neurotrophin receptors (Trks). Here, we extend this work by interrogating further the anatomy and function of the CMT2D sensory nervous system in mutantGarsmice, obtaining several key results: (1) sensory pathology is restricted to neurons innervating the hindlimbs; (2) perturbation of sensory development is not common to all mouse models of neuromuscular disease; (3)in vitroaxonal transport of signaling endosomes is not impaired in afferent neurons of all CMT2D mouse models; and (4)Garsexpression is selectively elevated in a subset of sensory neurons and linked to sensory developmental defects. These findings highlight the importance of comparative neurological assessment in mouse models of disease and shed light on key proposed neuropathogenic mechanisms inGARS1-linked neuropathy.

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