title: Pharmacological manipulation of gain-of-function and dominant-negative mechanisms in rhodopsin retinitis pigmentosa.
abstract: 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 (WT) 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 WT 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.
authors.affiliation: UCL Institute of Ophthalmology, London, UK.
authors.forename: Hugo F
authors.initials: HF
authors.lastname: Mendes
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
mesh_terms: D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D005799:Genes, Dominant / Q000187:drug effects*; D006801:Humans; D007287:Inorganic Chemicals / Q000494:pharmacology*; D009930:Organic Chemicals / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects; D017510:Protein Folding; D012174:Retinitis Pigmentosa / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology; D017299:Rod Opsins / Q000235:genetics / Q000378:metabolism*
chemical_list: D007287:Inorganic Chemicals; D009930:Organic Chemicals; D012176:Retinoids; D017299:Rod Opsins