HDAC3 Inhibition Stimulates Myelination in a CMT1A Mouse Model

Mol Neurobiol. 2022 Jun;59(6):3414-3430. doi: 10.1007/s12035-022-02782-x. Epub 2022 Mar 23.

Abstract

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.

Keywords: CMT1A; HDAC3 inhibition; Inflammation; Myelination; RGFP966; Schwann cell.

MeSH terms

  • Animals
  • Charcot-Marie-Tooth Disease* / genetics
  • Demyelinating Diseases* / metabolism
  • Disease Models, Animal
  • Histone Deacetylases / metabolism
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Rats
  • Schwann Cells / metabolism

Substances

  • Histone Deacetylases
  • histone deacetylase 3