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Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients

Seyed Yahya Anvar1, Peter AC 't Hoen1, Andrea Venema1, Barbara van der Sluijs2, Baziel van Engelen2, Marc Snoeck3, John Vissing4, Capucine Trollet56, George Dickson5, Aymeric Chartier7, Martine Simonelig7, Gert-Jan B van Ommen1, Silvere M van der Maarel1 and Vered Raz1*

Author Affiliations

1 Center for Human and Clinical Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands

2 Radboud University Nijmegen Medical Centre, Department of Neurology, Nijmegen, the Netherlands

3 Department of Anaesthesia, Canisius-Wilhelmina Hospital, Nijmegen, the Netherlands

4 Neuromuscular Research Unit and Department of Neurology, University of Copenhagen, Rigs Hospitalet, Denmark

5 School of Biological Sciences, Royal Holloway - University of London, Surrey, TW20 0EX, UK

6 INSERM U974, UMR 7215 CNRS, Institut de Myologie, UM 76 Université Pierre et Marie Curie, Paris, France

7 Institut de Genetique Humaine, CNRS UPR1142, 141 rue de la Cardonille, 34396 Montpellier Cedex 5, France

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Skeletal Muscle 2011, 1:15  doi:10.1186/2044-5040-1-15

Published: 4 April 2011


Oculopharyngeal muscular dystrophy (OPMD) is a late-onset progressive muscle disorder caused by a poly-alanine expansion mutation in the Poly(A) Binding Protein Nuclear 1 (PABPN1). The molecular mechanisms that regulate disease onset and progression are largely unknown. In order to identify molecular pathways that are consistently associated with OPMD, we performed an integrated high-throughput transcriptome study in affected muscles of OPMD animal models and patients. The ubiquitin-proteasome system (UPS) was found to be the most consistently and significantly OPMD-deregulated pathway across species. We could correlate the association of the UPS OPMD-deregulated genes with stages of disease progression. The expression trend of a subset of these genes is age-associated and therefore, marks the late onset of the disease, and a second group with expression trends relating to disease-progression. We demonstrate a correlation between expression trends and entrapment into PABPN1 insoluble aggregates of OPMD-deregulated E3 ligases. We also show that manipulations of proteasome and immunoproteasome activity specifically affect the accumulation and aggregation of mutant PABPN1. We suggest that the natural decrease in proteasome expression and its activity during muscle aging contributes to the onset of the disease.