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

TY - JOUR

T1 - Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients

AU - Anvar, Seyed Yahya

AU - hoen, Peter Ac

AU - Venema, Andrea

AU - van der Sluijs, Barbara

AU - van Engelen, Baziel

AU - Snoeck, Marc

AU - Vissing, John

AU - Trollet, Capucine

AU - Dickson, George

AU - Chartier, Aymeric

AU - Simonelig, Martine

AU - van Ommen, Gert-Jan B

AU - van der Maarel, Silvere M

AU - Raz, Vered

PY - 2011/4/4

Y1 - 2011/4/4

N2 - 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.

AB - 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.

U2 - http://dx.doi.org/10.1186/2044-5040-1-15

DO - http://dx.doi.org/10.1186/2044-5040-1-15

M3 - Journal article

SN - 2044-5040

VL - 1

SP - 15

JO - Skeletal Muscle

JF - Skeletal Muscle

IS - 1

ER -