From the Montreal Neurological Institute and Hospital (A.A.-B., P.D., G.R.), Ingram School of Nursing, Faculty of Medicine (S.R.), and Department of Neurology and Neurosurgery (G.R.), McGill University, Montreal; CHUM Research Center (A.P.), Montreal; Department of Neuroscience (A.P.), and Ophthalmology Research Hôpital Maisonneuve Rosemont, Laboratoire de Isabelle Brunette (J.L.), University of Montreal; Neuromuscular Group (B.B.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and Brain C-lab (C.N.), Institute of Biology Paris-Seine, CNRS UMR 8256 Biology of Adaptation & Aging, University Pierre and Marie Curie, Paris, France.
Neurology. 2018 Aug 7;91(6):e551-e561. doi: 10.1212/WNL.0000000000005942. Epub 2018 Jul 13.
To explore valproic acid (VPA) as a potentially beneficial drug in cellular and worm models of oculopharyngeal muscular dystrophy (OPMD).
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 OPMD model expressing human mutant PABPN1.
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 Alanines worms.
Our results suggest that VPA helps to counteract OPMD-related phenotypes in the cellular and disease models.
探讨丙戊酸（VPA）在眼咽型肌营养不良症（OPMD）的细胞和线虫模型中作为一种潜在有益药物的作用。
我们采用活细胞成像和生化测定相结合的方法，在稳定的 C2C12 肌营养不良症细胞模型、来自 OPMD 患者的淋巴母细胞系和表达人突变 PABPN1 的转基因 OPMD 模型中，评估了 VPA 的潜在保护作用。
我们证明 VPA 可对抗突变 PABPN1 的毒性。值得注意的是，我们发现 VPA 通过增加组蛋白的乙酰化水平，对 C2C12 细胞的存活、增殖和分化发挥长期的保护作用。此外，VPA 可提高源自 OPMD 患者的淋巴母细胞系中的组蛋白乙酰化水平。此外，用中等浓度的 VPA 处理线虫可显著改善 Alanines 线虫的运动能力。
我们的研究结果表明，VPA 有助于在细胞和疾病模型中对抗 OPMD 相关表型。
