Abstract
The P23H mutation in the rhodopsin gene causes rhodopsin misfolding, altered trafficking and formation of insoluble aggregates leading to photoreceptor degeneration and autosomal dominant retinitis pigmentosa (RP). There are no effective therapies to treat this condition. Compounds that enhance dissociation of protein aggregates may be of value in developing new treatments for such diseases. Anti-protein aggregating activity of curcumin has been reported earlier. In this study we present that treatment of COS-7 cells expressing mutant rhodopsin with curcumin results in dissociation of mutant protein aggregates and decreases endoplasmic reticulum stress. Furthermore we demonstrate that administration of curcumin to P23H-rhodopsin transgenic rats improves retinal morphology, physiology, gene expression and localization of rhodopsin. Our findings indicate that supplementation of curcumin improves retinal structure and function in P23H-rhodopsin transgenic rats. This data also suggest that curcumin may serve as a potential therapeutic agent in treating RP due to the P23H rhodopsin mutation and perhaps other degenerative diseases caused by protein trafficking defects.
Highlights
Retinal degenerations are a group of heterogeneous diseases of the retina, which result in irreversible blindness
Disruption of protein aggregates by curcumin To assess the effect of curcumin on protein aggregation, COS-7 cells expressing wt or mutant (P23H-R) rhodopsin with V5 tag were supplemented with 5 mM concentration of curcumin and analyzed for the presence of protein aggregates by immunocytochemistry followed by fluorescent microscopy
Treatment with curcumin or vehicle had no affect on localization pattern of wild type rhodopsin.These data indicate that curcumin treatment may alter the subcellular distribution pattern of mutant rhodopsin
Summary
Retinal degenerations are a group of heterogeneous diseases of the retina, which result in irreversible blindness. RP affects around 1.5 million people worldwide This disease can be inherited in autosomal dominant, autosomal recessive, X-linked or syndromic forms [4]. Rhodopsin is a G-protein coupled receptor and the most abundant protein in rod photoreceptor cells It consists of the polypeptide opsin and a single covalently bound molecule of the chromophore, 11-cis retinal. Class 1 mutant proteins are expressed at levels similar to the wild type rhodopsin, form the rhodopsin chromophore with 11-cis retinal and are transported to the cell surface. Class III mutants are expressed at low levels, remain in the endoplasmic reticulum (ER) and form rhodopsin chromophore poorly, cause abnormal trafficking of the protein and result in the formation of aggregates which are retained near the endoplasmic reticulum [8,9,10]. The P23H missense mutation is a class-III mutant and accounts for the largest fraction of cases in the world due to rhodopsin mutations [6,7,11]
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