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Songhua Li, Minghao Jin; Deletion of FATP4 in Rpe65-null rd12 mice improves cone vision but not rod vision. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1894 – A0040.
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© ARVO (1962-2015); The Authors (2016-present)
We recently showed that deletion of fatty acid transport protein-4 (FATP4) significantly promotes cone opsin solubility, cone photoreceptor survival, and cone-mediated vision in the RPE65 R91W knock-in mouse model of Leber congenital amaurosis (LCA). The purpose of this study was to test whether FATP4-deficiency can improve cone survival and function in RPE65-null rd12 mice.
Using rd12 and Fatp4-/-;Ivl-Fatp4tg/+ (shown as Fatp4-/- hereafter) mice, we generated rd12;Fatp4-/- mice. Key visual cycle enzymes and FATP4 in the retinal pigment epithelium (RPE) of these mice were detected by immunoblot analysis. Synthesis of 11-cis-retinal (11cRAL) in dark adapted mice were analyzed by high-performance liquid chromatography. Retinal degeneration was assessed by immunoblot and immunohistochemical analyses of rod and cone specific proteins. Visual functions of rod and cone photoreceptors were determined by scotopic and photopic electroretinographies (ERG) evoked with various flash intensities of white, 530-nm green or 360-nm UV light. For recording cone ERGs, animals were light adapted for 10 min by exposing to 40 cd/m2 white light.
RPE65 was undetectable in the both rd12 and rd12;Fatp4-/- RPEs while FATP4 was expressed only in the rd12 RPE. Expression levels of lecithin:retinol acyltransferase in the rd12 RPE were similar to those in age matched rd12;Fatp4-/- RPE. Similar to rd12 mice, dark adapted rd12;Fatp4-/- mice contained undetectable 11cRAL. Both immunoblotting and immunohistochemistry showed that the expression levels of rhodopsin in 2- and 4-month-old rd12 mice were similar to those in age-matched rd12;Fatp4-/- mice whereas the expression levels of M-opsin and cone arrestin in the rd12;Fatp4-/- mouse retina were significantly higher than those in the rd12 retina. Consistent with these results, rd12 and rd12;Fatp4-/- mice exhibited comparable scotopic ERG responses whereas green light-evoked ERG responses of M-cones were clearly greater in rd12;Fatp4-/- mice as compared to rd12 mice.
Our results indicate that 1) cone survival and function are supported by a RPE65-independent mechanism(s) that may be an important therapeutic target for LCA caused by loss of RPE65 function; and 2) FATP4 negatively regulates this RPE65-independent pathway.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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