Aida Abu-Baker1, Alex Parker1, Siriram Ramalingam1, Janet Laganiere1, Bernard Brais1, Christian Neri1, Patrick Dion1, Guy Rouleau2. 1. 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. 2. 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. guy.rouleau@mcgill.ca.
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.
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.
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