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Abstract
Objective To explore valproic acid (VPA) as a potentially beneficial drug in cellular and worm models of oculopharyngeal muscular dystrophy (OPMD).
Methods Using a combination of live cell imaging and biochemical measures, we evaluated the potential protective effect of VPA in a stable C2C12 muscle cell model of OPMD, in lymphoblastoid cell lines derived from patients with OPMD and in a transgenic Caenorhabditis elegans OPMD model expressing human mutant PABPN1.
Results We demonstrated that VPA protects against the toxicity of mutant PABPN1. Of note, we found that VPA confers its long-term protective effects on C2C12 cell survival, proliferation, and differentiation by increasing the acetylated level of histones. Furthermore, VPA enhances the level of histone acetylation in lymphoblastoid cell lines derived from patients with OPMD. Moreover, treatment of nematodes with moderate concentrations of VPA significantly improved the motility of the PABPN-13 Alanines worms.
Conclusions Our results suggest that VPA helps to counteract OPMD-related phenotypes in the cellular and C elegans disease models.
Glossary
- DM=
- differentiation medium;
- DMEM=
- Dulbecco's modified Eagle medium;
- expPABPN1=
- expanded PABPN1;
- FFC=
- fluorescence flow cytometry;
- GFP=
- green fluorescent protein;
- HAT=
- histone acetyltransferase;
- HDAC=
- histone deacetylase;
- LCL=
- lymphoblastoid cell line;
- OPMD=
- oculopharyngeal muscular dystrophy;
- polyAla=
- polyalanine;
- RPMI=
- Roswell Park Memorial Institute medium;
- SMA=
- spinal muscular atrophy;
- VPA=
- valproic acid;
- wt=
- wild-type
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
- Received October 25, 2017.
- Accepted in final form May 8, 2018.
- © 2018 American Academy of Neurology
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