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O. L. Moritz, A. Qazalbash, H.-C. Lee, B. M. Tam; Spectral Sensitivity of Light-induced Retinal Degeneration in a Xenopus Laevis Model of Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2290.
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The rhodopsin mutation P23H is the most common cause of autosomal dominant retinitis pigmentosa (RP) in North America. Previous studies of patients and animal models indicate that the photoreceptor death associated with expression of the mutant protein is exacerbated by light exposure. This effect of light is in turn due to the influence of the photosensitive rhodopsin chromophore on biosynthesis and ER export of the mutant protein. In order to better understand the mechanisms involved, we have characterized the light sensitivity of retinal degeneration in a Xenopus laevis model of RP based on the rhodopsin P23H mutation, in which the associated retinal degeneration is completely rescued by preventing light exposure.
We characterized the sensitivity of retinal degeneration to varying intensities, wavelengths, and durations of light exposure. Animals were reared under cyclic light of various intensities, with light provided by either a white light source, filtered white light, or single wavelength sources (i.e. light emitting diodes) ranging from UV to red. The effect of varying the duration of light exposure during the 24 hour cycle was also examined. Retinal degeneration was assessed by dot blot for total rhodopsin levels, and by histology.
Retinal degeneration was most severe following long exposures to green light, and could be prevented by using filters that block shorter wavelengths, or by reducing the duration of light exposure, even if light intensity was increased proportionately.
Based on the known spectral properties of rhodopsin and free chromophore, our results indicate that the mechanism that initiates retinal degeneration involves destabilization of rhodopsin in the biosynthetic pathway due to photoisomerization or loss of chromophore from folded P23H rhodopsin, rather than a limitation in chromophore supply or a defect in protein folding. These results have important implications for the design of RP therapies involving pharmacological chaperones, or protection of patients from light.
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