Human Molecular Genetics Advance Access published online on July 17, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn202
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Pharmacological manipulation of gain-of-function and dominant-negative mechanisms in rhodopsin retinitis pigmentosa
UCL Institute of Ophthalmology, London, UK
* Corresponding Author: Professor Mike Cheetham, UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK email michael.cheetham{at}ucl.ac.uk Tel +44(0)20 7608 6944 Fax +44(0)20 7608 4002
Received April 25, 2008; Revised June 20, 2008; Accepted July 11, 2008
Mutations in the dim light photoreceptor protein rod opsin cause autosomal dominant retinitis pigmentosa. The majority of these mutations (class II) lead to protein misfolding. For example, the common class II rod opsin mutation P23H misfolds and is retained in the ER, prior to retrotranslocation and degradation by the proteasome. If degradation fails then the protein can aggregate to form intracellular inclusions. Furthermore, mutant opsin exerts a dominant negative effect on the wild-type protein. Here we show that the toxic gain of function and dominant negative properties of misfolded rod opsin in cells can be alleviated by drug treatments targeted against a range of cellular pathways. P23H rod opsin aggregation, inclusion formation with associated caspase activation and cell death were reduced by kosmotropes, molecular chaperone inducers and mToR inhibition. But these treatments did not enhance mutant opsin folding or reduce the dominant negative effect of P23H rod opsin. In contrast, retinoids acted as pharmacological chaperones to enhance P23H folding and reduce the dominant negative effect on wild-type rod opsin processing, as well as reducing toxic gains of function. Therefore, the suppression of the dominant negative effects of protein misfolding required enhanced folding of the mutant protein, whereas suppression of toxic gain of function effects did not require improved folding per se. These studies suggest that some forms of rhodopsin RP may be treated by targeting protein folding and reducing protein aggregation.