Rdh8, an all-trans-retinol dehydrogenase, is crucial in the retinoid cycle. It functions to reduce all-trans-retinal, a reactive aldehyde released by photoactivated rhodopsin, to all-trans-retinol (vitamin A) in vertebrate rod photoreceptors. This process is essential for vision as it helps clear toxic by-products of the retinoid cycle [5]. Rdh8 also participates in vitamin A (retinol) metabolism, which may be related to biological processes associated with hypertension [2].

In Rdh8 -/- Abca4 -/- and Rdh8 -/- Rdh12 -/- Abca4 -/- mice, there is slowly progressive, severe retinal degeneration under room light conditions, and intense light-induced acute retinal degeneration in Rdh8 -/- Rdh12 -/- Abca4 -/- mice. The amount of A2E, a condensation product related to human macular degeneration, in the retinal pigment epithelium (RPE) of these mice correlates with diminished all-trans-retinal clearance, with the highest A2E amounts found in Rdh8 -/- Rdh12 -/- Abca4 -/- mice. This indicates that Rdh8, along with Rdh12 and Abca4, protects the retina and reduces A2E production by facilitating all-trans-retinal clearance [3]. Light-exposed Abca4 -/- Rdh8 -/- mice, which display severe defects in all-trans-retinal clearance, serve as models for dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1). In these mice, activation of heme oxygenase-1 (HO-1) and eukaryotic translation initiation factor 2α (eIF2α) contributes to photoreceptor cell death and retinal degeneration [1,4].

In conclusion, Rdh8 is essential for reducing all-trans-retinal in photoreceptor cells, thereby protecting the retina from damage caused by the accumulation of toxic retinoid by-products. Gene-knockout mouse models, especially Abca4 -/- Rdh8 -/- mice, have been instrumental in understanding the role of Rdh8 in the pathogenesis of dry AMD and STGD1, highlighting its significance in these retinal diseases [1,3,4].

References:

1. Chen, Chao, Yang, Kunhuan, He, Danxue, Chen, Jingmeng, Wu, Yalin. 2022. Induction of ferroptosis by HO-1 contributes to retinal degeneration in mice with defective clearance of all-trans-retinal. In Free radical biology & medicine, 194, 245-254. doi:10.1016/j.freeradbiomed.2022.12.008. https://pubmed.ncbi.nlm.nih.gov/36509314/

2. Jiang, Wenxi, Wang, Xizi, Li, Ronghui, Jia, Xiaodong, Gu, Mingliang. 2021. Targeted capture sequencing identifies genetic variations of GRK4 and RDH8 in Han Chinese with essential hypertension in Xinjiang. In PloS one, 16, e0255311. doi:10.1371/journal.pone.0255311. https://pubmed.ncbi.nlm.nih.gov/34297769/

3. Maeda, Akiko, Golczak, Marcin, Maeda, Tadao, Palczewski, Krzysztof. 2009. Limited roles of Rdh8, Rdh12, and Abca4 in all-trans-retinal clearance in mouse retina. In Investigative ophthalmology & visual science, 50, 5435-43. doi:10.1167/iovs.09-3944. https://pubmed.ncbi.nlm.nih.gov/19553623/

4. He, Danxue, Tao, Lei, Cai, Binxiang, Liu, Zuguo, Wu, Yalin. 2023. eIF2α incites photoreceptor cell and retina damage by all-trans-retinal. In The Journal of biological chemistry, 299, 104686. doi:10.1016/j.jbc.2023.104686. https://pubmed.ncbi.nlm.nih.gov/37031820/

5. Chen, Chunhe, Thompson, Debra A, Koutalos, Yiannis. 2012. Reduction of all-trans-retinal in vertebrate rod photoreceptors requires the combined action of RDH8 and RDH12. In The Journal of biological chemistry, 287, 24662-70. doi:10.1074/jbc.M112.354514. https://pubmed.ncbi.nlm.nih.gov/22621924/