Ablation of fatty acid transport protein-4 enhances cone survival, M-cone vision, and synthesis of cone-tropic 9--retinal in 12 mouse model of Leber congenital amaurosis

Document Type

Article

Publication Date

5-29-2024

Publication Title

The Journal of Neuroscience

Abstract

The canonical visual cycle employing RPE65 as the retinoid isomerase regenerates 11--retinal to support both rod- and cone-mediated vision. Mutations of are associated with Leber congenital amaurosis (LCA) that results in rod and cone photoreceptor degeneration and vision loss of affected patients at an early age. Dark-reared mouse has been known to form isorhodopsin that employs 9--retinal as the photosensitive chromophore. The mechanism regulating 9--retinal synthesis and the role of the endogenous 9--retinal in cone survival and function remain largely unknown. In the present study, we found that ablation of fatty acid transport protein-4 (FATP4), a negative regulator of 11--retinol synthesis catalyzed by RPE65, increased the formation of 9--retinal, but not 11--retinal, in a light-independent mechanism in both sexes of RPE65-null 12 mice. Both 12 and 12; mice contained a massive amount of all--retinyl esters in the eyes, exhibited comparable scotopic vision and rod degeneration. However, expression levels of M- and S-opsins as well as numbers of M- and S-cones surviving in the superior retinas of 12; mice were at least 2-fold greater than those in age-matched 12 mice. Moreover, FATP4-deficiency significantly shortened photopic -wave implicit time, improved M-cone visual function and substantially deaccelerated the progression of cone degeneration in 12 mice, whereas FATP4-deficiency in mice with wild-type alleles neither induced 9--retinal formation nor influenced cone survival and function. These results identify FATP4 as a new regulator of synthesis of 9--retinal, which is a "cone-tropic" chromophore supporting cone survival and function in the retinas with defective RPE65. Isorhodopsin, which employs 9--retinal as the light-sensitive chromophore, is known to support rod survival and function in dark-reared mouse model of LCA that exhibits early cone degeneration. The mechanism regulating 9--retinal formation and the role of 9--retinal in cone survival remain largely unknown. Here, we identified FATP4 as a new negative regulator of 9--retinal synthesis in RPE65-null mice. We further found that increased 9--retinal synthesis did not influence rod function and degeneration, but it significantly enhanced cone survival and function in mice lacking both RPE65 and FATP4. Our findings indicate that 9--retinal functions as a "cone-tropic" chromophore, providing 9--retinal and FATP4 as important therapeutic targets to alleviate cone degeneration and loss of daytime color vision in RPE65 mutation-associated LCA.

PubMed ID

38811164

Link to Full Text

Share

COinS