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

Abstract

Dominant, missense mutations in the widely and constitutively expressed GARS1 gene 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-causing Gars mutations 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 mutant Gars mice, 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 vitro axonal transport of signaling endosomes is not impaired in afferent neurons of all CMT2D mouse models; and (4) Gars expression 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 in GARS1 -linked neuropathy.

Characterization of somatosensory neuron involvement in the SOD1G93A mouse model

“…Whereas the skin innervation showed a reduced number of IENF, affecting both peptidergic and non-peptidergic fibers (present results) and also reduced innervation of Meissner corpuscles in SOD1 G93A mice 9 , DRG analyses showed that different sensory populations are preserved, with only a marginal decrease of double positive neurons (CGRP+ and IB4+) at 12 weeks. These findings are in line with previous work that studied two sensory neuron populations in the DRG of SOD1 G93A mice 50 , and also reported no differences of nociceptive and mechanoreceptor/proprioceptor sensory neuronal populations between the mutant mice and the WT at 30 and 100 days of age.…”

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

“…Identification of such factors may elucidate pathomechanisms and provide potential targetable pathways. While we did not observe upper limb weakness in mutant Gars mice (possible reasons for which are discussed elsewhere 35 ), we do observe significant distinctions in NMJ pathology between (FDB, red). The schematic was created with BioRender (https://biorender.…”

“…Mutant Gars mice display a developmental perturbation of sensory neuron fate in hindlimb-innervating lumbar dorsal root ganglia (DRG) 17 , which is not present in forelimb-innervating cervical DRG 35 , suggestive of lengthdependent phenotypes in CMT2D mice. To determine whether the neuromuscular system displays a similar pathological pattern, we performed grip strength testing of mild Gars C201R/+ mice 27 .…”

Sensory Involvement in Amyotrophic Lateral Sclerosis

“…Although both neuronal cultures showed abnormalities, neurites grew significantly slower in TDP43 A315T neurons and were more sensitive to vincristine than SOD1 G93A cells [ 98 ]. However, although subcellular and functional changes have been described, sensory DRG populations are preserved over time [ 99 ] while their distal axons in the skin are already reduced [ 100 ], suggesting distal sensory axonopathy, similar to what has already been described in the motor component of the disease [ 101 ] ( Figure 2 ).…”

“…Pathological studies confirmed that the degeneration of the dorsal columns occurs in up to half of patients, especially in lumbar regions, including both genetic ( SOD1 ) and sporadic forms [ 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 ]. The predominant involvement of lumbar spinal cord segments in both functional and pathological examinations suggests an axonal length-dependent degeneration, taking as a starting point cortical and subcortical brain structures, as suggested by the corticofugal propagation proposed by Braak [ 77 ].…”