Linked Life Data

12082151

Source:http://linkedlifedata.com/resource/pubmed/id/12082151

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
Pt 14
pubmed:dateCreated
2002-6-25
pubmed:abstractText
Mutations in the photopigment rhodopsin are the major cause of autosomal dominant retinitis pigmentosa. The majority of mutations in rhodopsin lead to misfolding of the protein. Through the detailed examination of P23H and K296E mutant opsin processing in COS-7 cells, we have shown that the mutant protein does not accumulate in the Golgi, as previously thought, instead it forms aggregates that have many of the characteristic features of an aggresome. The aggregates form close to the centrosome and lead to the dispersal of the Golgi apparatus. Furthermore, these aggregates are ubiquitinated, recruit cellular chaperones and disrupt the intermediate filament network. Mutant opsin expression can disrupt the processing of normal opsin, as co-transfection revealed that the wild-type protein is recruited to mutant opsin aggregates. The degradation of mutant opsin is dependent on the proteasome machinery. Unlike the situation with DeltaF508-CFTR, proteasome inhibition does not lead to a marked increase in aggresome formation but increases the retention of the protein within the ER, suggesting that the proteasome is required for the efficient retrotranslocation of the mutant protein. Inhibition of N-linked glycosylation with tunicamycin leads to the selective retention of the mutant protein within the ER and increases the steady state level of mutant opsin. Glycosylation, however, has no influence on the biogenesis and targeting of wild-type opsin in cultured cells. This demonstrates that N-linked glycosylation is required for ER-associated degradation of the mutant protein but is not essential for the quality control of opsin folding. The addition of 9-cis-retinal to the media increased the amount of P23H, but not K296E, that was soluble and reached the plasma membrane. These data show that rhodopsin autosomal dominant retinitis pigmentosa is similar to many other neurodegenerative diseases in which the formation of intracellular protein aggregates is central to disease pathogenesis, and they suggest a mechanism for disease dominance.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0021-9533
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
115
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2907-18
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:12082151-Animals, pubmed-meshheading:12082151-COS Cells, pubmed-meshheading:12082151-Cell Membrane, pubmed-meshheading:12082151-Cysteine Endopeptidases, pubmed-meshheading:12082151-Eukaryotic Cells, pubmed-meshheading:12082151-Glycosylation, pubmed-meshheading:12082151-Golgi Apparatus, pubmed-meshheading:12082151-Inclusion Bodies, pubmed-meshheading:12082151-Microscopy, Electron, pubmed-meshheading:12082151-Molecular Chaperones, pubmed-meshheading:12082151-Multienzyme Complexes, pubmed-meshheading:12082151-Mutation, pubmed-meshheading:12082151-Organelles, pubmed-meshheading:12082151-Proteasome Endopeptidase Complex, pubmed-meshheading:12082151-Protein Folding, pubmed-meshheading:12082151-Protein Transport, pubmed-meshheading:12082151-Retinaldehyde, pubmed-meshheading:12082151-Retinitis Pigmentosa, pubmed-meshheading:12082151-Rhodopsin, pubmed-meshheading:12082151-Tunicamycin, pubmed-meshheading:12082151-Ubiquitin
pubmed:year
2002
pubmed:articleTitle
The cellular fate of mutant rhodopsin: quality control, degradation and aggresome formation.
pubmed:affiliation
Division of Pathology, Institute of Ophthalmology, University College London, UK.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't