Continuous regeneration of 11-
cis-retinal, the chromophore of visual pigments in photoreceptor cells, is essential for vision.
7 This process occurs through the retinoid cycle that operates in both the retinal pigmented epithelium (RPE) and photoreceptors.
8 9 After 11-
cis-retinal is photoisomerized to all-
trans-retinal, most of the all-
trans-retinal is shuttled to the outside of the photoreceptor discs by ABCA4, a transporter localized in the rims of photoreceptor discs.
10 RDH8 is one of the main enzymes that reduces all-
trans-retinal to all-
trans- retinol in rod and cone outer segments.
11 Thus, both ABCA4 and RDH8 are involved in all-
trans-retinal clearance in photoreceptors. Any delay in this process leads to accumulation of all-
trans-retinal and conjugate products, such as di-retinoid-pyridinium-ethanolamine (A2E), in both photoreceptors and the RPE.
12 13 As previously reported,
Rdh8 −/− Abca4 −/− mice display cone–rod dystrophy by the age of 4 to 6 weeks and display light-dependant progressive retinal degeneration as well.
4 Retinal degeneration in this mouse model mimics most of the clinical features of human AMD, including lipofuscin accumulation, drusen formation, basal laminar hyaline deposition, RPE cell death, complement activation, and eventual choroidal neovascularization (CNV). Therefore, these animals provide an excellent surrogate model for human AMD in which to test candidate therapeutics.