Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular homeostasis

Sleigh, James N.; Gómez-Martín, A; Wei, Na; Bai, Ge; Yang, Xiang‐Lei; Schiavo, Giampietro

doi:10.1038/s41598-017-10005-w

Cited by 24 publications

(25 citation statements)

References 59 publications

(104 reference statements)

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“…Muscles were dissected and stained as wholemount preparations as outlined formerly 30,31 . The following antibodies were used to costain pre-synaptic motor nerve terminals and axons: 1/25 mouse pan anti-synaptic vesicle 2 (SV2, Developmental Studies Hybridoma Bank [DSHB], Iowa City, IA, supernatant) and 1/250 mouse anti-neurofilament (2H3, DSHB, supernatant).…”

Section: Muscle Dissection and Immunohistochemistrymentioning

confidence: 99%

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

Sleigh

Mech

Schiavo

2020

Preprint

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Dominantly inherited, missense mutations in the widely expressed housekeeping gene, GARS1, cause Charcot-Marie-Tooth type 2D (CMT2D), a peripheral neuropathy characterised by muscle weakness and wasting in limb extremities. Mice modelling CMT2D display early and selective neuromuscular junction (NMJ) pathology, epitomised by disturbed maturation and neurotransmission, leading to denervation. Indeed, the NMJ disruption has been reported in several different muscles; however, a systematic comparison of neuromuscular synapses from distinct body locations has yet to be performed. We therefore analysed NMJ development and degeneration across five different wholemount muscles to identify key synaptic features contributing to the distinct pattern of neurodegeneration in CMT2D mice. Denervation was found to occur along a distal-to-proximal gradient, providing a cellular explanation for the greater weakness observed in mutant Gars hindlimbs compared to forelimbs. Nonetheless, muscles from similar locations and innervated by axons of equivalent length showed significant differences in neuropathology, suggestive of additional factors impacting on sitespecific neuromuscular degeneration. Defective NMJ development preceded and associated with degeneration, but was not linked to a delay of wild-type NMJ maturation processes. Correlation analyses indicate that muscle fibre type nor synaptic architecture explain the differential denervation of CMT2D NMJs, rather it is the extent of post-natal synaptic growth that predisposes to neurodegeneration. Together, this work improves our understanding of the mechanisms driving synaptic vulnerability in CMT2D and hints at pertinent pathogenic pathways.

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Section: Muscle Dissection and Immunohistochemistrymentioning

confidence: 99%

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

Sleigh

Mech

Schiavo

2020

Preprint

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“…This model is supported by a genetic interaction between Gars P234KY/ϩ and Nrp1 ϩ/Ϫ mice, and by the rescue of motor performance deficits of the CMT2D mice through VEGF overexpression. Interestingly, CMT2D mice do not exhibit defects in the vasculature system (76,90).…”

Section: Glyrs Cmt Mutants Interact With Nrp1/plexin Trk and Hdac6mentioning

confidence: 99%

Neurodegenerative Charcot–Marie–Tooth disease as a case study to decipher novel functions of aminoacyl-tRNA synthetases

Wei

Zhang

Yang

2019

Journal of Biological Chemistry

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Edited by Karin Musier-Forsyth Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that catalyze the first reaction in protein biosynthesis, namely the charging of transfer RNAs (tRNAs) with their cognate amino acids. aaRSs have been increasingly implicated in dominantly and recessively inherited human diseases. The most common aaRS-associated monogenic disorder is the incurable neurodegenerative disease Charcot-Marie-Tooth neuropathy (CMT), caused by dominant mono-allelic mutations in aaRSs. With six currently known members (GlyRS, TyrRS, AlaRS, HisRS, TrpRS, and MetRS), aaRSs represent the largest protein family implicated in CMT etiology. After the initial discovery linking aaRSs to CMT, the field has progressed from understanding whether impaired tRNA charging is a critical component of this disease to elucidating the specific pathways affected by CMTcausing mutations in aaRSs. Although many aaRS CMT mutants result in loss of tRNA aminoacylation function, animal genetics studies demonstrated that dominant mutations in GlyRS cause CMT through toxic gain-of-function effects, which also may apply to other aaRS-linked CMT subtypes. The CMT-causing mechanism is likely to be multifactorial and involves multiple cellular compartments, including the nucleus and the extracellular space, where the normal WT enzymes also appear. Thus, the association of aaRSs with neuropathy is relevant to discoveries indicating that aaRSs also have nonenzymatic regulatory functions that coordinate protein synthesis with other biological processes. Through genetic, functional, and structural analyses, commonalities among different mutations and different aaRS-linked CMT subtypes have begun to emerge, providing insights into the nonenzymatic functions of aaRSs and the pathogenesis of aaRS-linked CMT to guide therapeutic development to treat this disease.

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“…To analyse Gars C201R/+ transport in early symptomatic sensory neurons, we cultured primary thoracic and lumbar DRG neurons from one and three month old mice and assessed retrograde signalling endosome trafficking. These spinal levels were combined to obtain sufficient cell numbers for the assay (Figure 1B), and the timepoints were chosen to allow comparison with several other phenotypes assessed previously in this model (Sleigh et al, 2014b(Sleigh et al, , 2017a(Sleigh et al, , 2017b. Cultures were incubated with fluorescently labelled atoxic binding fragment of tetanus neurotoxin (HCT-647), which is taken up by neurons and loaded into signalling endosomes containing Trk receptors and p75 neurotrophin receptor (p75NTR), when applied to media (Deinhardt et al, 2006(Deinhardt et al, , 2007.…”

Section: Long-range Signalling Endosome Transport Is Unaffected In CMmentioning

confidence: 99%

Altered sensory neuron development in CMT2D mice is site-specific and linked to increased GlyRS levels

Sleigh

Mech

Aktar

et al. 2020

Preprint

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Dominant, missense mutations in the widely and constitutively expressed GARS1 gene cause a 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 in mouse models of neuromuscular disease; 3) in vitro axonal transport of signalling 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.

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Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular homeostasis

Cited by 24 publications

References 59 publications

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

Neurodegenerative Charcot–Marie–Tooth disease as a case study to decipher novel functions of aminoacyl-tRNA synthetases

Altered sensory neuron development in CMT2D mice is site-specific and linked to increased GlyRS levels

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