Raising cGMP restores proteasome function and myelination in mice with a proteotoxic neuropathy

VerPlank, Jordan J. S.; Gawron, Joseph; Silvestri, Nicholas J.; Feltri, M. Laura; Wrabetz, Lawrence; Goldberg, Alfred L.

doi:10.1093/brain/awab249

Cited by 8 publications

(16 citation statements)

References 52 publications

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“…We predict that IFB-088-mediated translational attenuation through persistent phosphorylation of eIF2α, will better enable Schwann cells to target R98C P0 to the proteosome, readjusting protein homeostasis as shown in MpzSer63del mice [11,12]. In support of this hypothesis, it has been recently shown that promoting degradation by stimulating the proteasome ameliorates proteostasis and improves the phenotype of MpzSer63del mice [66]. We have previously shown that UPR activation causes MpzR98C and MpzS63del Schwann cells to enter a limited differentiation state in part by upregulating C-Jun expression; c-Jun, a transcription factor, negatively regulates myelination [50] [16].…”

Section: How Alleviating Er-stress Improves the Neuropathy Caused By The R98c And Ser63delmentioning

confidence: 78%

Treatment with IFB-088 improves neuropathy in CMT1A and CMT1B mice

Bai

Treins

Volpi

et al. 2021

Preprint

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Charcot Marie Tooth diseases type 1A (CMT1A), caused by duplication of Peripheral Myelin Protein 22 (PMP22) gene, and CMT1B, caused by mutations in myelin protein zero (MPZ) gene are the two most common forms of demyelinating CMT (CMT1) and no treatments are available for either. Prior studies of the MpzSer63del mouse model of CMT1B have demonstrated that protein misfolding, endoplasmic reticulum (ER) retention and activation of the unfolded protein response (UPR) contributed to the neuropathy. Heterozygous patients with an arginine to cysteine mutation in MPZ (MPZR98C) develop a severe infantile form of CMT1B which is modeled by MpzR98C/+ mice that also show ER-stress and an activated UPR. C3-PMP22 mice are considered to effectively model CMT1A. Altered proteostasis, ER-stress and activation of the UPR have been demonstrated in mice carrying Pmp22 mutations. To determine whether enabling the ER-stress/UPR and readjusting protein homeostasis would effectively treat these models of CMT1B and CMT1A we administered Sephin1/IFB-088/icerguestat, a UPR modulator which showed efficacy in the MpzS63del model of CMT1B, to heterozygous MpzR98C and C3-PMP22 mice. Mice were analyzed by behavioral, neurophysiological, morphological and biochemical measures. Both MpzR98C/+ and C3-PMP22 mice improved in motor function and neurophysiology. Myelination, as demonstrated by g-ratios and myelin thickness, improved in CMT1B and CMT1A mice and markers of UPR activation returned towards wild type values. Taken together our results demonstrate the capability of IFB-088 to treat a second mouse model of CMT1B and a mouse model of CMT1A, the most common form of CMT. Given the recent benefits of IFB-088 treatment in Amyotrophic Lateral Sclerosis and Multiple Sclerosis animal models, these data demonstrate its potential in managing UPR and ER-stress for multiple mutations in CMT1 as well as in other neurodegenerative diseases.

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Section: How Alleviating Er-stress Improves the Neuropathy Caused By The R98c And Ser63delmentioning

confidence: 78%

Treatment with IFB-088 improves neuropathy in CMT1A and CMT1B mice

Bai

Treins

Volpi

et al. 2021

Preprint

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“…We predict that IFB-088-mediated translational attenuation through persistent phosphorylation of eIF2α will better enable Schwann cells to target R98C P0 for degradation, readjusting protein homeostasis as shown in Mpz Ser63del mice [ 24 , 28 ]. In support of this hypothesis, it has been recently shown that promoting degradation by stimulating the proteasome ameliorates proteostasis and improves the phenotype of Mpz Ser63del mice [ 51 ]. We have previously shown that UPR activation causes Mpz R98C and Mpz S63del Schwann cells to enter a limited differentiation state in part by upregulating C-Jun expression; c-Jun, a transcription factor, negatively regulates myelination [ 37 , 52 ].…”

Section: Discussionmentioning

confidence: 98%

Treatment with IFB-088 Improves Neuropathy in CMT1A and CMT1B Mice

Bai

Treins

Volpi³

et al. 2022

Mol Neurobiol

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Charcot-Marie-Tooth disease type 1A (CMT1A), caused by duplication of the peripheral myelin protein 22 (PMP22) gene, and CMT1B, caused by mutations in myelin protein zero (MPZ) gene, are the two most common forms of demyelinating CMT (CMT1), and no treatments are available for either. Prior studies of the MpzSer63del mouse model of CMT1B have demonstrated that protein misfolding, endoplasmic reticulum (ER) retention and activation of the unfolded protein response (UPR) contributed to the neuropathy. Heterozygous patients with an arginine to cysteine mutation in MPZ (MPZR98C) develop a severe infantile form of CMT1B which is modelled by MpzR98C/ + mice that also show ER stress and an activated UPR. C3-PMP22 mice are considered to effectively model CMT1A. Altered proteostasis, ER stress and activation of the UPR have been demonstrated in mice carrying Pmp22 mutations. To determine whether enabling the ER stress/UPR and readjusting protein homeostasis would effectively treat these models of CMT1B and CMT1A, we administered Sephin1/IFB-088/icerguestat, a UPR modulator which showed efficacy in the MpzS63del model of CMT1B, to heterozygous MpzR98C and C3-PMP22 mice. Mice were analysed by behavioural, neurophysiological, morphological and biochemical measures. Both MpzR98C/ + and C3-PMP22 mice improved in motor function and neurophysiology. Myelination, as demonstrated by g-ratios and myelin thickness, improved in CMT1B and CMT1A mice and markers of UPR activation returned towards wild-type values. Taken together, our results demonstrate the capability of IFB-088 to treat a second mouse model of CMT1B and a mouse model of CMT1A, the most common form of CMT. Given the recent benefits of IFB-088 treatment in amyotrophic lateral sclerosis and multiple sclerosis animal models, these data demonstrate its potential in managing UPR and ER stress for multiple mutations in CMT1 as well as in other neurodegenerative diseases. Graphical Abstract (Left panel) the accumulation of overexpressed PMP22 or misfolded mutant P0 in the Schwann cell endoplasmic reticulum (ER) leads to overwhelming of the degradative capacity, activation of ER-stress mechanisms, and myelination impairment. (Right panel) by prolonging eIF2α phosphorylation, IFB-088 reduces the amount of newly synthesized proteins entering the ER, allowing the protein quality control systems to better cope with the unfolded/misfolded protein and allowing myelination to progress.

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“…120 Molecules such as Gluc-Nac, which stimulate PQC mechanisms have been shown to improve myelination in DRG explants from CMT1B models. 120 In line with this, a recent work has shown that in vivo treatment of Mpz S63del mice with agents like sildenafil, which raises cyclic guanosine monophosphate (cGMP) and activates proteasome activities, protein ubiquitination and degradation of misfolded proteins, improved myelination, and nerve conduction velocities, 49 suggesting that compounds capable of increasing cGMP could be useful therapies for CMT1B and proteotoxic neuropathies in general.…”

Section: Targeting Protein Misfolding In Demyelinating Cmtmentioning

confidence: 83%

Recent advances in the treatment of Charcot‐Marie‐Tooth neuropathies

Bolino

D’Antonio

2023

J Peripheral Nervous Sys

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Charcot‐Marie‐Tooth (CMT) neuropathies are one of the most common neuromuscular disorders. However, despite the identification of more than 100 causative genes, therapeutic options are still missing. The generation of authentic animal models and the increasing insights into the understanding of disease mechanisms, in addition to extraordinary developments in gene and molecular therapies, are quickly changing this scenario, and several strategies are currently being translated, or are getting close to, clinical trials. Here, we provide an overview of the most recent advances for the therapy of CMT at both the preclinical and clinical levels. For clarity, we have grouped the approaches in three different categories: gene therapy based on viral‐mediated delivery, molecular therapies based on alternative delivery systems, and pharmacological therapies.

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Raising cGMP restores proteasome function and myelination in mice with a proteotoxic neuropathy

Cited by 8 publications

References 52 publications

Treatment with IFB-088 improves neuropathy in CMT1A and CMT1B mice

Treatment with IFB-088 improves neuropathy in CMT1A and CMT1B mice

Treatment with IFB-088 Improves Neuropathy in CMT1A and CMT1B Mice

Recent advances in the treatment of Charcot‐Marie‐Tooth neuropathies

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