title: Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients.
abstract: 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.
authors.affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, P,O, Box 9600, 2300 RC Leiden, the Netherlands.
authors.forename: Seyed Yahya
authors.initials: SY
authors.lastname: Anvar
authors.forename: Peter Ac
authors.initials: PA
authors.lastname: 't Hoen
authors.forename: Andrea
authors.initials: A
authors.lastname: Venema
authors.forename: Barbara
authors.initials: B
authors.lastname: van der Sluijs
authors.forename: Baziel
authors.initials: B
authors.lastname: van Engelen
authors.forename: Marc
authors.initials: M
authors.lastname: Snoeck
authors.forename: John
authors.initials: J
authors.lastname: Vissing
authors.forename: Capucine
authors.initials: C
authors.lastname: Trollet
authors.forename: George
authors.initials: G
authors.lastname: Dickson
authors.forename: Aymeric
authors.initials: A
authors.lastname: Chartier
authors.forename: Martine
authors.initials: M
authors.lastname: Simonelig
authors.forename: Gert-Jan B
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: Silvere M
authors.initials: SM
authors.lastname: van der Maarel
authors.forename: Vered
authors.initials: V
authors.lastname: Raz