Résumé :
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Oculopharyngeal muscular dystrophy (OPMD) is a late onset disease characterized by eyelid dropping, swallowing difficulties and limb weakness. Alanine expansions in the coding region of poly(A) binding protein N1 (PABPN1) resulting from GCG trinucleotide repeat extensions lead to the dominant autosomal inheritance of OPMD. In skeletal muscle fibers of OPMD patients, mutant PABPN1 protein aggregates as fibrillar nuclear inclusions, which are the hallmark of the disease. We have generated a Drosophila model that recapitulates muscular phenotypes with similarities to those of OPMD: i) muscle degeneration ii) fibrillar nuclear inclusions containing PABPN1 in muscle nuclei (Chartier et al., EMBO J. 2006). Molecular analysis of this model showed that muscle disorder in Drosophila is induced by an intrinsic toxicity of PABPN1 brought by the RNA binding domain and enhanced by the alanine expansions. We investigated the potential of single-chain intracellular antibody (intrabody) as therapeutic agent for OPMD. We could induce muscle expression of several intrabodies against PABPN1 (Verhensen et al., HMG 2006), in the Drosophila OPMD model and we found that several of them can prevent PABPN1 toxicity and muscular phenotypes.
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