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HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model

Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy, with currently no effective treatment or cure. CMT1A is caused by a duplication of the PMP22 gene, which leads to Schwann cell differentiation defects and dysmyelination of the peripheral nerves. The epigenetic reg...

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Autores principales: Prior, Robert, Verschoren, Stijn, Vints, Katlijn, Jaspers, Tom, Rossaert, Elisabeth, Klingl, Yvonne E., Silva, Alessio, Hersmus, Nicole, Van Damme, Philip, Van Den Bosch, Ludo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9148289/
https://www.ncbi.nlm.nih.gov/pubmed/35320455
http://dx.doi.org/10.1007/s12035-022-02782-x
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author Prior, Robert
Verschoren, Stijn
Vints, Katlijn
Jaspers, Tom
Rossaert, Elisabeth
Klingl, Yvonne E.
Silva, Alessio
Hersmus, Nicole
Van Damme, Philip
Van Den Bosch, Ludo
author_facet Prior, Robert
Verschoren, Stijn
Vints, Katlijn
Jaspers, Tom
Rossaert, Elisabeth
Klingl, Yvonne E.
Silva, Alessio
Hersmus, Nicole
Van Damme, Philip
Van Den Bosch, Ludo
author_sort Prior, Robert
collection PubMed
description Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy, with currently no effective treatment or cure. CMT1A is caused by a duplication of the PMP22 gene, which leads to Schwann cell differentiation defects and dysmyelination of the peripheral nerves. The epigenetic regulator histone deacetylase 3 (HDAC3) has been shown to negatively regulate myelination as well as its associated signaling pathways, PI3K-AKT and MAPK-ERK. We showed that these signaling pathways are indeed downregulated in the C3-PMP22 mouse model, similar to what has been shown in the CMT1A rat model. We confirmed that early postnatal defects are present in the peripheral nerves of the C3-PMP22 mouse model, which led to a progressive reduction in axon caliber size and myelination. The aim of this study was to investigate whether pharmacological HDAC3 inhibition could be a valuable therapeutic approach for this CMT1A mouse model. We demonstrated that early treatment of CMT1A mice with the selective HDAC3 inhibitor RGFP966 increased myelination and myelin g-ratios, which was associated with improved electrophysiological recordings. However, a high dose of RGFP966 caused a decline in rotarod performance and a decline in overall grip strength. Additionally, macrophage presence in peripheral nerves was increased in RGFP966 treated CMT1A mice. We conclude that HDAC3 does not only play a role in regulating myelination but is also important in the neuroimmune modulation. Overall, our results indicate that correct dosing of HDAC3 inhibitors is of crucial importance if translated to a clinical setting for demyelinating forms of CMT or other neurological disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-022-02782-x.
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spelling pubmed-91482892022-05-30 HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model Prior, Robert Verschoren, Stijn Vints, Katlijn Jaspers, Tom Rossaert, Elisabeth Klingl, Yvonne E. Silva, Alessio Hersmus, Nicole Van Damme, Philip Van Den Bosch, Ludo Mol Neurobiol Article Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy, with currently no effective treatment or cure. CMT1A is caused by a duplication of the PMP22 gene, which leads to Schwann cell differentiation defects and dysmyelination of the peripheral nerves. The epigenetic regulator histone deacetylase 3 (HDAC3) has been shown to negatively regulate myelination as well as its associated signaling pathways, PI3K-AKT and MAPK-ERK. We showed that these signaling pathways are indeed downregulated in the C3-PMP22 mouse model, similar to what has been shown in the CMT1A rat model. We confirmed that early postnatal defects are present in the peripheral nerves of the C3-PMP22 mouse model, which led to a progressive reduction in axon caliber size and myelination. The aim of this study was to investigate whether pharmacological HDAC3 inhibition could be a valuable therapeutic approach for this CMT1A mouse model. We demonstrated that early treatment of CMT1A mice with the selective HDAC3 inhibitor RGFP966 increased myelination and myelin g-ratios, which was associated with improved electrophysiological recordings. However, a high dose of RGFP966 caused a decline in rotarod performance and a decline in overall grip strength. Additionally, macrophage presence in peripheral nerves was increased in RGFP966 treated CMT1A mice. We conclude that HDAC3 does not only play a role in regulating myelination but is also important in the neuroimmune modulation. Overall, our results indicate that correct dosing of HDAC3 inhibitors is of crucial importance if translated to a clinical setting for demyelinating forms of CMT or other neurological disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-022-02782-x. Springer US 2022-03-23 2022 /pmc/articles/PMC9148289/ /pubmed/35320455 http://dx.doi.org/10.1007/s12035-022-02782-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Prior, Robert
Verschoren, Stijn
Vints, Katlijn
Jaspers, Tom
Rossaert, Elisabeth
Klingl, Yvonne E.
Silva, Alessio
Hersmus, Nicole
Van Damme, Philip
Van Den Bosch, Ludo
HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model
title HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model
title_full HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model
title_fullStr HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model
title_full_unstemmed HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model
title_short HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model
title_sort hdac3 inhibition stimulates myelination in a cmt1a mouse model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9148289/
https://www.ncbi.nlm.nih.gov/pubmed/35320455
http://dx.doi.org/10.1007/s12035-022-02782-x
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