P.354 - Nuclear PABPN1 aggregates in OPMD: correlation study and therapy

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease manifested primarily by progressive weakness of the eyelid and pharyngeal muscles, leading to ptosis and dysphagia. A short abnormal triplet expansion in the polyA-binding protein nuclear 1 (PABPN1) gene leads to the accumulation of nuclear insoluble aggregates in muscles of OPMD patients. While the roles of PABPN1 in post-transcriptional gene regulation are established, the molecular basis of OPMD and the exact contribution of these PABPN1 aggregates remain poorly understood. We are currently investigating the role they might have in the pathology, searching triggers that induce their formation, and testing drugs to remove them. Using a large collection of OPMD patient's muscle biopsies, we are evaluating the percentage, size and characteristics of these aggregates using immunofluorescent and electronic microscopy. Any potential correlation of these parameters with age and genotype is carefully monitored. Results obtained so far suggest an increase in the percentage of nuclear aggregates together with age. Although there are controversies regarding the role of aggregates in OPMD, it is commonly accepted that aggregates and/or the early oligomeric species are toxic (Abu-Baker et al., 2013; Davies et al., 2006). Decreasing their number in OPMD models greatly ameliorate the muscle phenotype. Within the frame of an European OPMD network, we are testing drugs to reduce aggregate formation. Among them, guanabenz acetate (GA) has been identified as a good candidate in drosophila OPMD model (Barbezier et al., 2011). Here we show that GA is also efficient in cell and mouse OPMD models: treatment with GA decreases the percentage of nuclear aggregates and ameliorates muscle strength and atrophy in mice. Altogether these studies will shed light on the exact contribution of aggregate in OPMD and help design potential therapeutic targets.