%0 Journal Article
%T Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients
%A Seyed Anvar
%A Peter AC 't Hoen
%A Andrea Venema
%A Barbara van der Sluijs
%A Baziel van Engelen
%A Marc Snoeck
%A John Vissing
%A Capucine Trollet
%A George Dickson
%A Aymeric Chartier
%A Martine Simonelig
%A Gert-Jan B van Ommen
%A Silvere M van der Maarel
%A Vered Raz
%J Skeletal Muscle
%D 2011
%I BioMed Central
%R 10.1186/2044-5040-1-15
%X Oculopharyngeal muscular dystrophy (OPMD) is a late-onset progressive muscle disorder for which the underlying molecular mechanisms are largely unknown. This autosomal dominant muscular dystrophy has an estimated prevalence of 1 in 100,000 worldwide [1]. A higher prevalence has been reported in the Jewish Caucasian and French-Canadian populations (1 in 600 and 1 in 1,000, respectively) [2,3]. OPMD is caused by expansion of a homopolymeric alanine (Ala) stretch at the N-terminus of the Poly(A) Binding Protein Nuclear 1 (PABPN1) by two to seven additional Ala residues [4]. Although PABPN1 is ubiquitously expressed, the clinical and pathological features of OPMD are restricted to a subset of skeletal muscles, causing progressive ptosis, dysphagia, and limb muscle weakness. In affected muscles, the expanded PABPN1 (expPABPN1) accumulates in intranuclear inclusions (INI) [5]. Animal models for OPMD were generated in Drosophila, mice and Caenorhabditis elegans with a muscle-specific expression of expPABPN1 [6-8]. These models recapitulate INI formation and progressive muscle weakness in OPMD, and a correlation between INI formation and muscle weakness has been reported [6-8]. In these OPMD models protein disaggregation approaches attenuate muscle symptoms [8-10]. So far, however, the molecular mechanisms that are associated with OPMD onset and progression are not known. Previously, we performed transcriptome analysis on skeletal muscles from a mouse model of OPMD and found massive gene deregulation, which was reflected by a broad spectrum of altered cellular pathways [11]. We found an association of transcriptional changes with muscle atrophy [11]. Muscle atrophy was recently reported in homozygous OPMD patients [2]. However, the vast majority of OPMD patients are heterozygous and muscle atrophy is not a common pathological characteristic of the disease in its early stages. Importantly, a mouse model with low and constitutive expPABPN1 expression exhibits minor muscle def
%U http://www.skeletalmusclejournal.com/content/1/1/15