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| Status |
Public on Apr 19, 2011 |
| Title |
Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset progressive muscle disorder caused by a poly-alanine expansion mutation in PABPN1. The hallmark of OPMD is the accumulation of the mutant protein in insoluble nuclear inclusions. The molecular mechanisms associated with disease onset and progression are unknown. We performed a high-throughput cross-species transcriptome study of affected muscles from two OPMD animal models and from patients at pre-symptomatic and symptomatic stages. The most consistently and significantly OPMD-deregulated pathway across species is the ubiquitin-proteasome system (UPS). By analyzing expression profiles, we found that the majority of OPMD-deregulated genes are age-associated. Based on expression trends, disease onset can be separated from progression; the expression profiles of the proteasome-encoding genes are associated with onset but not with progression. In a muscle cell model, proteasome inhibition and the stimulation of immunoproteasome specifically affect the accumulation and aggregation of mutant PABPN1. We suggest that proteasome down-regulation during muscle aging triggers the accumulation of expPABPN1 that in turn enhances proteasome deregulation and leads to intranuclear inclusions (INI) formation.
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| Overall design |
Human quadriceps muscle samples were collected with the needle or by an open surgical procedure from OPMD patients and family members as well as from anonymous age-matching healthy individuals that gave informed consent. The presence of expansion mutation in PABPN1 in OPMD patients and pre-symptomatic was determined with sequencing. Bergstrom needle biopsies from the (pre)symptomatic patients were approved by the ethical committee. Total RNA was extracted from skeletal muscles using RNA Bee (Amsbio) according to the manufacturer's instructions. RNA integration number (RIN) was determined with RNA 6000 Nano (Agilent Technologies). RNA with RIN >7 were used for subsequent steps. RNA labeling was performed with the Illumina® TotalPrep RNA Amplification kit (Ambion) according to the manufacturer's protocol, and subsequently was hybridized to Illumina Human v3 Bead arrays.
SUBMITTER_CITATION: Anvar, S.Y., 't Hoen, P.A.C., Venema, A., van der Sluijs, B., van Engelen, B., Snoeck, M., Vissing, J., Trollet, C., Dickson, G., Chartier, A. et al. (2011). Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients. Skeletal Muscle 1:15
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| Contributor(s) |
Anvar SY, 't Hoen PA, Venema A, van der Sluijs B, van Engelen B, Snoeck M, Vissing J, Trollet C, Dickson G, Chartier A, Simonelig M, van Ommen GB, van der Maarel SM, Raz V |
| Citation(s) |
21798095, 23793615, 22072955 |
| Submission date |
Jan 13, 2011 |
| Last update date |
Mar 09, 2020 |
| Contact name |
Seyed Yahya Anvar |
| E-mail(s) |
s.y.anvar@lumc.nl
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| Phone |
0031715269489
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| Organization name |
Leiden University Medical Center
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| Department |
Center for Human and Clinical Genetics
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| Street address |
Einthovenweg 20
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| City |
Leiden |
| ZIP/Postal code |
2300RC |
| Country |
Netherlands |
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| Platforms (1) |
| GPL6884 |
Illumina HumanWG-6 v3.0 expression beadchip |
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| Samples (26)
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| Relations |
| BioProject |
PRJNA136213 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE26605_HumanData_Normalized_Pre-Symptomatic_Patients_and_age-matching_Controls.txt.gz |
2.4 Mb |
(ftp)(http) |
TXT |
| GSE26605_HumanData_Normalized_Symptomatic_Patients_and_age-matching_Controls.txt.gz |
2.4 Mb |
(ftp)(http) |
TXT |
| GSE26605_HumanRawDataset1.txt.gz |
14.8 Mb |
(ftp)(http) |
TXT |
| GSE26605_HumanRawDataset2.txt.gz |
13.4 Mb |
(ftp)(http) |
TXT |
| GSE26605_RAW.tar |
6.3 Mb |
(http)(custom) |
TAR |
| Processed data included within Sample table |
| Processed data are available on Series record |
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