Transferrin ameliorates retinal degeneration by mediating the dimerization of all-trans-retinal

High levels of all-trans-retinal (atRAL) in the retina is considered to be responsible for the development of autosomal recessive Stargardt's disease (STGD1) and dry age-related macular degeneration (dAMD). Two bisretinoids, all-trans-retinal dimer (atRAL-dimer) and N-retinyl-N-retinylidene ethanolamine (A2E), form from the dimerization of atRAL in the retina but they possess much lower toxicity and phototoxicity toward retinal pigment epithelium (RPE) cells than atRAL. Here, we introduced a novel function of transferrin (TRF) in mediating the conversion of atRAL into atRAL-dimer and A2E, which effectively protected the retina from damage by atRAL and prevented retinal function decline in mice, and rescued atRAL-loaded RPE cells. Moreover, TRF-mediated conversion of atRAL to atRAL-dimer and A2E required the help of bicarbonate ions (HCO₃^-). atRAL had the capacity to stimulate the expression of TRF in RPE and photoreceptor cells as well as RPE/choroid and neural retina of mice, reflecting that the elevation of TRF levels by atRAL is most likely to help defy level increase and cytotoxicity of atRAL through facilitating its dimerization and thereby serves as a mechanism of retinal self-protection. Our findings offer a promising avenue for the treatment of retinopathies characterized by disrupted clearance of atRAL.