New evidence for secondary axonal degeneration in demyelinating neuropathies

Moss, Kathryn R.; Bopp, Taylor S.; Johnson, Anna E.; Höke, Ahmet

doi:10.1016/j.neulet.2020.135595

Cited by 34 publications

(39 citation statements)

References 642 publications

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“…Our results agree with previous data observed in another CMT4H mouse model, using a different promoter (Dhh) to drive Cre recombinase expression in SCs (Horn, Baumann et al 2012). In our Fgd4 SC-/model, we also provided, for the first time, evidence of late axonal degeneration reflected by late muscle denervation of the gastrocnemius of 12 months old mutant mice, a phenomenon previously described in various de/dysmyelinating CMT (Previtali, Quattrini et al 2007, Moss, Bopp et al 2021 . Gait test revealed that Fgd4 SC-/mice display late motor impairment, resulting in the decrease of the pressure exerted by forepaws.…”

Section: Discussionsupporting

confidence: 91%

Imbalance of Neuregulin1-ErbB2/3 signaling underlies altered myelin homeostasis in models of Charcot-Marie-Tooth disease type 4H

El-Bazzal

Ghata

Estève

et al. 2022

Preprint

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Charcot Marie Tooth disease (CMT) is one of the most common inherited neurological disorders, affecting either axons from the motor and/or sensory neurons or Schwann cells (SC) of the peripheral nervous system, and caused by more than 100 genes. We previously identified mutations in FGD4, as responsible for CMT4H, an autosomal recessive demyelinating form of CMT. FGD4 encodes FRABIN a GDP/GTP nucleotide exchange factor (GEF), particularly for the small GTPase cdc42. Remarkably, nerves from patients with CMT4H display excessive redundant myelin called outfoldings that arise from focal hypermyelination, suggesting that FRABIN could play a role in the control of PNS myelination. To gain insights into the role of FGD4/FRABIN in SC myelination, we generated a knock-out mouse model, with conditional ablation of fgd4 in SC. We showed that the specific deletion of FRABIN in SCs leads to aberrant myelination in vitro, in dorsal root ganglion (DRG)/SCs cocultures as well in vivo, in distal sciatic nerves. We observed that those myelination defects are related to an upregulation of some interactors of the NRG1 type III/ErbB2/3 signaling pathway, which is known to ensure a proper level of myelination in the PNS. Based on a yeast two- hybrid screen, we identified SNX3 as a new partner of FRABIN, which is involved in the regulation of endocytic trafficking. Interestingly, we showed that loss of FRABIN impairs endocytic trafficking which may contribute to the defective NRG1 type III/ErbB2/3 signaling and myelination. Finally, we showed that the reestablishment of proper levels of the NRG1 type III/ErbB2/3 pathway using Niacin treatment reduces myelin outfoldings in nerves of CMT4H mice. Overall, our work reveals a new role of FRABIN in the regulation of NRG1 type III/ErbB2/3 NRG1signaling and myelination and opens future therapeutic strategies based on the modulation of NRG1 type III/ErbB2/3 NRG1to reduce CMT4H pathology and more generally others demyelinating CMT.

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Section: Discussionsupporting

confidence: 91%

Imbalance of Neuregulin1-ErbB2/3 signaling underlies altered myelin homeostasis in models of Charcot-Marie-Tooth disease type 4H

El-Bazzal

Ghata

Estève

et al. 2022

Preprint

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“…Although our results suggest that SARM1 knockout does not rescue CMT1A deficits, there are several factors that require further consideration. C3‐PMP mice and additional CMT1A rodent models 40 exhibit dramatically reduced CMAP amplitudes and clinical phenotypes early on, but our nerve and muscle morphometry do not support an abundance of secondary axon degeneration. Therefore, these phenotypes must be caused by prolonged dysmyelination and consequent conduction block.…”

Section: Discussionmentioning

confidence: 59%

SARM1 knockout does not rescue neuromuscular phenotypes in a Charcot‐Marie‐Tooth disease Type 1A mouse model

Moss¹,

Johnson²,

Bopp

et al. 2022

J Peripheral Nervous Sys

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Charcot-Marie-Tooth disease Type 1A (CMT1A) is caused by duplication of the PMP22 gene and is the most common inherited peripheral neuropathy. Although CMT1A is a dysmyelinating peripheral neuropathy, secondary axon degeneration has been suggested to drive functional deficits in patients. Given that SARM1 knockout is a potent inhibitor of the programmed axon degeneration pathway, we asked whether SARM1 knockout rescues neuromuscular phenotypes in CMT1A model (C3-PMP) mice. CMT1A mice were bred with SARM1 knockout mice to generate CMT1A/SARM1 À/À mice. A series of behavioral assays were employed to evaluate motor and sensorimotor function. Electrophysiological and histological studies of the tibial branch of the sciatic nerve were performed. Additionally, gastrocnemius and soleus muscle morphology were evaluated histologically. Although clear behavioral and electrophysiological deficits were observed in CMT1A model mice, genetic deletion of SARM1 conferred no significant improvement. Nerve morphometry revealed predominantly myelin deficits in CMT1A model mice and SARM1 knockout yielded no improvement in all nerve morphometry measures. Similarly, muscle morphometry deficits in CMT1A model mice were not improved by SARM1 knockout. Our findings demonstrate that programmed axon degeneration pathway inhibition does not provide therapeutic benefit in C3-PMP CMT1A model mice. Our results indicate that the clinical phenotypes observed in CMT1A mice are likely caused primarily by prolonged dysmyelination, motivate further investigation into mechanisms of dysmyelination in these mice and necessitate the development of improved CMT1A rodent models that recapitulate the secondary axon degeneration observed in patients.

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“…21 Possible suggested mechanisms for secondary axon degeneration in CMT1A include altered microtubule cargo transport and cytoskeleton organization, and reduced ciliary neurotrophic factor and neurotrophin-3 expression. 21,23,33,34…”

Section: Discussionmentioning

confidence: 99%

Pathology of the peripheral neuropathy Charcot-Marie-Tooth disease type 4H in Holstein Friesian cattle with a splice site mutation in FGD4

et al. 2022

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Charcot-Marie-Tooth disease (CMT) is a hereditary sensory and motor peripheral neuropathy that is one of the most common inherited neurological diseases of humans and may be caused by mutations in a number of different genes. The subtype Charcot-Marie-Tooth disease type 4H (CMT4H) is caused by homozygous mutations in the FGD4 (FYVE, RhoGEF, and PH domain-containing 4) gene. A previous genome-wide association study involving 130,783 dairy cows found 6 novel variants, one of which was a homozygous splice site mutation in the FGD4 gene. Descendants of carriers were genotyped to identify 9 homozygous Holstein Friesian calves that were raised to maturity, of which 5 were euthanized and sampled for histopathology and electron microscopy at 2 and 2.5 years of age. Three control Holstein Friesian animals were raised with the calves and euthanized at the same time points. No macroscopic lesions consistent with CMT4H were seen at necropsy. Microscopically, peripheral nerves were hypercellular due to hyperplasia of S100-positive Schwann cells, and there was onion bulb formation, axonal degeneration with demyelination, and increased thickness of the endoneurium. On electron microscopy, decreased axonal density, onion bulb formations, myelin outfoldings, and increased numbers of mitochondria were present. These changes are consistent with those described in mouse models and humans with CMT4H, making these cattle a potential large animal model for CMT.

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New evidence for secondary axonal degeneration in demyelinating neuropathies

Cited by 34 publications

References 642 publications

Imbalance of Neuregulin1-ErbB2/3 signaling underlies altered myelin homeostasis in models of Charcot-Marie-Tooth disease type 4H

Imbalance of Neuregulin1-ErbB2/3 signaling underlies altered myelin homeostasis in models of Charcot-Marie-Tooth disease type 4H

SARM1 knockout does not rescue neuromuscular phenotypes in a Charcot‐Marie‐Tooth disease Type 1A mouse model

Pathology of the peripheral neuropathy Charcot-Marie-Tooth disease type 4H in Holstein Friesian cattle with a splice site mutation in FGD4

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