Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients
<p>Abstract</p> <p>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 u...
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Series: | Skeletal Muscle |
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doaj-8c74646d6e7c44c8b4ee02757f4704842020-11-24T22:06:38ZengBMCSkeletal Muscle2044-50402011-04-01111510.1186/2044-5040-1-15Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patientsAnvar Seyed't Hoen Peter ACVenema Andreavan der Sluijs Barbaravan Engelen BazielSnoeck MarcVissing JohnTrollet CapucineDickson GeorgeChartier AymericSimonelig Martinevan Ommen Gert-Jan Bvan der Maarel Silvere MRaz Vered<p>Abstract</p> <p>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.</p> http://www.skeletalmusclejournal.com/content/1/1/15 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Anvar Seyed 't Hoen Peter AC Venema Andrea van der Sluijs Barbara van Engelen Baziel Snoeck Marc Vissing John Trollet Capucine Dickson George Chartier Aymeric Simonelig Martine van Ommen Gert-Jan B van der Maarel Silvere M Raz Vered |
spellingShingle |
Anvar Seyed 't Hoen Peter AC Venema Andrea van der Sluijs Barbara van Engelen Baziel Snoeck Marc Vissing John Trollet Capucine Dickson George Chartier Aymeric Simonelig Martine van Ommen Gert-Jan B van der Maarel Silvere M Raz Vered Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients Skeletal Muscle |
author_facet |
Anvar Seyed 't Hoen Peter AC Venema Andrea van der Sluijs Barbara van Engelen Baziel Snoeck Marc Vissing John Trollet Capucine Dickson George Chartier Aymeric Simonelig Martine van Ommen Gert-Jan B van der Maarel Silvere M Raz Vered |
author_sort |
Anvar Seyed |
title |
Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients |
title_short |
Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients |
title_full |
Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients |
title_fullStr |
Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients |
title_full_unstemmed |
Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients |
title_sort |
deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in opmd animal models and patients |
publisher |
BMC |
series |
Skeletal Muscle |
issn |
2044-5040 |
publishDate |
2011-04-01 |
description |
<p>Abstract</p> <p>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.</p> |
url |
http://www.skeletalmusclejournal.com/content/1/1/15 |
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