HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model.

Robert Prior, Stijn Verschoren, Katlijn Vints, Tom Jaspers, Elisabeth Rossaert, Yvonne E Klingl, Alessio Silva, Nicole Hersmus, Philip Van Damme, Ludo Van Den Bosch

Molecular neurobiology 2022 Jun

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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. © 2022. The Author(s).

Citation

Robert Prior, Stijn Verschoren, Katlijn Vints, Tom Jaspers, Elisabeth Rossaert, Yvonne E Klingl, Alessio Silva, Nicole Hersmus, Philip Van Damme, Ludo Van Den Bosch. HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model. Molecular neurobiology. 2022 Jun;59(6):3414-3430