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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., (© 2018 American Academy of Neurology.)

Oculopharyngeal muscular dystrophy (OPMD) is a late onset disorder characterized by progressive weakening of specific muscles. It is caused by short expansions of the N-terminal polyalanine tract in the poly(A) binding protein nuclear 1 (PABPN1), and it belongs to the group of protein aggregation diseases, such as Huntington's, Parkinson's and Alzheimer diseases. Mutant PABPN1 forms nuclear aggregates in diseased muscles in both patients and animal models. Intrabodies are antibodies that are modified to be expressed intracellularly and target specific antigens in subcellular locations. They are commonly generated by artificially linking the variable domains of antibody heavy and light chains. However, natural single-chain antibodies are produced in Camelids and, when engineered, combined the advantages of being single-chain, small sized and very stable. Here, we determine the in vivo efficiency of Llama intrabodies against PABPN1, using the established Drosophila model of OPMD. Among six anti-PABPN1 intrabodies expressed in muscle nuclei, we identify one as a strong suppressor of OPMD muscle degeneration in Drosophila, leading to nearly complete rescue. Expression of this intrabody affects PABPN1 aggregation and restores muscle gene expression. This approach promotes the identification of intrabodies with high therapeutic value and highlights the potential of natural single-chain intrabodies in treating protein aggregation diseases.

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant form of late-onset muscular dystrophy. Ptosis (droopy eyelids) and dysphagia (difficulty swallowing) are the most common presenting symptoms. The purpose of this phenomenological study was to describe the experience of living with OPMD. Purposeful sampling was used to recruit individuals with genetically confirmed OPMD who displayed ptosis and dysphagia, were 40 years or older, English speaking, and were willing to consent to the tape-recording of the interviews. An unstructured interview format was used to solicit the participants' perspectives of living with droopy eyelids, difficulty swallowing, and a genetic disorder. The interviews were audiotaped and transcribed verbatim. Colaizzi's Method was used to analyze the data, which identified five comprehensive themes. The themes that emerged describing the experience of living with OPMD were "Adjusting to Change", "Managing Misconceptions", "Seeking Normality", "Facing the Future", and "Informing Children". The information derived from this study will assist nurses to identify the burdens of living with OPMD and to intervene appropriately early in the course of the disease.