Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C

Cipriani, Silvia; Phan, Vietxuan; Médard, Jean-Jacques; Horvath, Rita; Lochmüller, Hanns; Chrast, Roman; Roos, Andreas; Spendiff, Sally

doi:10.3390/ijms19124072

Cited by 24 publications

(27 citation statements)

References 55 publications

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“…A more detailed analysis performed in our study demonstrated also the percentage of fully and partially innervated NMJs in this model. Comparison of the Cx32 KO mouse NMJ results and a recently published analysis of NMJ pathology in the CMT4C mouse model, shows similarities in NMJ area, diameter and perimeter but the CMT4C model shows an increase in post-synaptic fragmentation [39], that was not evaluated in our study, but may be indirectly reflected in the tendency for larger NMJ diameter in the mock compared to the fully treated Cx32 KO or the WT group.…”

Section: Discussionsupporting

confidence: 44%

Gene replacement therapy after neuropathy onset provides therapeutic benefit in a model of CMT1X

Kagiava

Richter

Tryfonos

et al. 2019

Human Molecular Genetics

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X-linked Charcot-Marie-Tooth disease (CMT1X), one of the commonest forms of inherited demyelinating neuropathy, results from GJB1 gene mutations causing loss of function of the gap junction protein connexin32 (Cx32). The aim of this study was to examine whether delayed gene replacement therapy after the onset of peripheral neuropathy can provide a therapeutic benefit in the Gjb1-null/Cx32 knockout model of CMT1X. After delivery of the LV-Mpz.GJB1 lentiviral vector by a single lumbar intrathecal injection into 6-month-old Gjb1-null mice, we confirmed expression of Cx32 in lumbar roots and sciatic nerves correctly localized at the paranodal myelin areas. Gjb1-null mice treated with LV-Mpz.GJB1 compared with LV-Mpz.Egfp (mock) vector at the age of 6 months showed improved motor performance at 8 and 10 months. Furthermore, treated mice showed increased sciatic nerve conduction velocities, improvement of myelination and reduced inflammation in lumbar roots and peripheral nerves at 10 months of age, along with enhanced quadriceps muscle innervation. Plasma neurofilament light (NEFL) levels, a clinically relevant biomarker, were also ameliorated in fully treated mice. Intrathecal gene delivery after the onset of peripheral neuropathy offers a significant therapeutic benefit in this disease model, providing a proof of principle for treating patients with CMT1X at different ages.

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Section: Discussionsupporting

confidence: 44%

Gene replacement therapy after neuropathy onset provides therapeutic benefit in a model of CMT1X

Kagiava

Richter

Tryfonos

et al. 2019

Human Molecular Genetics

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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] .…”

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.

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“…CMAP amplitude, however, expressed as root mean squared (RMS), was significantly lower in MCT4 À/À at all frequencies tested ( Figure 7D). Interestingly, loss of NMJ integrity and decreased CMAP amplitude have been described in patients with CMT (Elbracht et al, 2014) (Spaulding et al, 2016 (Cipriani et al, 2018). Together, these data suggest that ablation of MCT4 had a negative effect on the structural and functional stability of the motor unit.…”

Section: Loss Of Mct4 Leads To Degeneration Of the Nmj And Decreased mentioning

confidence: 74%

New Insights into the Lactate Shuttle: Role of MCT4 in the Modulation of the Exercise Capacity

et al. 2019

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Lactate produced by muscle during high-intensity activity is an important end product of glycolysis that supports whole body metabolism. The lactate shuttle model suggested that lactate produced by glycolytic muscle fibers is utilized by oxidative fibers. MCT4 is a proton coupled monocarboxylate transporter preferentially expressed in glycolytic muscle fibers and facilitates the lactate efflux. Here we investigated the exercise capacity of mice with disrupted lactate shuttle due to global deletion of MCT4 (MCT4 À/À) or muscle-specific deletion of the accessory protein Basigin (iMSBsg À/À). Although MCT4 À/À and iMSBsg À/À mice have normal muscle morphology and contractility, only MCT4 À/À mice exhibit an exercise intolerant phenotype. In vivo measurements of compound muscle action potentials showed a decrement in the evoked response in the MCT4 À/À mice. This was accompanied by a significant structural degeneration of the neuromuscular junctions (NMJs). We propose that disruption of the lactate shuttle impacts motor function and destabilizes the motor unit.

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Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C

Cited by 24 publications

References 55 publications

Gene replacement therapy after neuropathy onset provides therapeutic benefit in a model of CMT1X

Gene replacement therapy after neuropathy onset provides therapeutic benefit in a model of CMT1X

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

New Insights into the Lactate Shuttle: Role of MCT4 in the Modulation of the Exercise Capacity

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