Purpose.: Although the retinoid cycle is essential for vision, all-trans-retinal and the side products of this cycle are toxic. Delayed clearance of all-trans-retinal causes accumulation of its condensation products, A2E, and all-trans-retinal dimer (RALdi), both associated with human macular degeneration. The protective roles were examined of the all-trans-RDHs, Rdh8 and Rdh12, and the ATP-binding cassette transporter Abca4, retinoid cycle enzymes involved in all-trans-retinal clearance.

Methods.: Mice genetically engineered to lack Rdh8, Rdh12, and Abca4, either singly or in various combinations, were investigated because all-trans-retinal clearance is achieved by all-trans-RDHs and Abca4. Knockout mice were evaluated by spectral-domain optical coherence tomography (SD-OCT), electroretinography, retinal morphology, and visual retinoid profiling with HPLC and MS. ARPE19 cells were examined to evaluate A2E and RALdi oxidation and toxicity induced by exposure to UV and blue light.

Results.: Rdh8−/− Abca4−/− and Rdh8−/− Rdh12−/− Abca4−/− mice displayed slowly progressive, severe retinal degeneration under room light conditions. Intense light-induced acute retinal degeneration was detected by SD-OCT in Rdh8−/− Rdh12−/− Abca4−/− mice. Amounts of A2E in the RPE correlated with diminished all-trans-retinal clearance, and the highest A2E amounts were found in Rdh8−/− Rdh12−/− Abca4−/− mice. However oxidized A2E was not found in any of these mice, and A2E oxidation was not induced by blue light and UV illumination of A2E-loaded ARPE19 cells. Of interest, addition of all-trans-retinal did activate retinoic acid receptors in cultured cells.

Conclusions.: Rdh8, Rdh12, and Abca4 all protect the retina and reduce A2E production by facilitating all-trans-retinal clearance. Delayed all-trans-retinal clearance contributes more than A2E oxidation to light-induced cellular toxicity.