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Research Article |
1 Division of Pathology, Institute of Ophthalmology, University College London,
London, UK
2 Electron Microscopy, Institute of Ophthalmology, University College London,
London, UK
* Author for correspondence (e-mail: michael.cheetham{at}ucl.ac.uk )
Accepted 1 May 2002
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 
F508-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.
Key words: Rhodopsin, Aggresome, Proteasome, Chaperone, Glycosylation, Retinitis pigmentosa
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