Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models

Morelli, Kathryn H.; Griffin, Laurie B.; Pyne, Nettie K.; Wallace, Lindsay; Fowler, Allison M.; Oprescu, Stephanie N.; Takase, Ryuichi; Wei, Na; Meyer‐Schuman, Rebecca; Mellacheruvu, Dattatreya; Kitzman, Jacob O.; Kocen, Samuel G.; Hines, Timothy J.; Spaulding, Emily L.; Lupski, James R.; Nesvizhskii, Alexey I.; Mancías, Pedro; Butler, Ian J.; Yang, Xiang‐Lei; Hou, Ya‐Ming; Antonellis, Anthony; Harper, Scott Q.; Burgess, Robert W.

doi:10.1172/jci130600

Cited by 53 publications

(92 citation statements)

References 48 publications

(71 reference statements)

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“…The neuromuscular junction (NMJ) is the specialised synapse connecting lower motor neurons to muscle fibres, and is dysfunctional in several CMT models [20][21][22][23][24][25] . Indeed, CMT2D mice display loss of NMJ integrity in multiple hindlimb muscles without spinal cord motor neuron degeneration 9,[26][27][28][29][30] . By directly comparing a proximal and a distal muscle, we have previously shown that the neuromuscular synapse is an important site of selective and early pathology 28 , replicating the muscle weakness pattern of patients.…”

Section: Introductionmentioning

confidence: 99%

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

2020

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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 with forelimbs. Nonetheless, muscles from similar locations and innervated by axons of equivalent length showed significant differences in neuropathology, suggestive of additional factors impacting on site-specific 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: Introductionmentioning

confidence: 99%

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

2020

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“…Several different mouse models are available for CMT2D (Seburn et al, 2006 ; Achilli et al, 2009 ; Morelli et al, 2019 ), which have mutations in endogenous mouse Gars , causing phenotypes akin to human neuropathy. These mice display loss of lower motor neuron connectivity and disturbed neurotransmission at the neuromuscular junction (NMJ), causing muscle weakness and motor function deficits (Sleigh et al, 2014a ; Spaulding et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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

Sleigh

Mech

Aktar

et al. 2020

Front. Cell. Neurosci.

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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.

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“…The neuromuscular junction (NMJ) is the specialised synapse connecting lower motor neurons to muscle fibres, and is dysfunctional in several CMT subtype models [17][18][19][20][21][22] . Indeed, CMT2D mice display loss of NMJ integrity in multiple hindlimb muscles without spinal cord motor neuron degeneration 9,[23][24][25][26][27] . By directly comparing a proximal and a distal muscle, we have previously shown that the neuromuscular synapse is an important site of selective and early pathology 25 , replicating the muscle weakness pattern of patients.…”

Section: Introductionmentioning

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.

show abstract

Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models

Cited by 53 publications

References 48 publications

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

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

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

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