Ablation of Fatty Acid Transport Protein-4 Enhances Cone Survival, M-cone Vision, and Synthesis of Cone-Tropic 9- cis -Retinal in rd 12 Mouse Model of Leber Congenital Amaurosis.
| Autor: | Li S; Neuroscience Center, Louisiana State University School of Medicine, LSU Health New Orleans, New Orleans, Louisiana 70112., Jin M; Neuroscience Center, Louisiana State University School of Medicine, LSU Health New Orleans, New Orleans, Louisiana 70112 mjin@lsuhsc.edu.; Department of Ophthalmology, Louisiana State University School of Medicine, LSU Health New Orleans, New Orleans, Louisiana 70112. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2024 Jul 03; Vol. 44 (27). Date of Electronic Publication: 2024 Jul 03. |
| DOI: | 10.1523/JNEUROSCI.1994-23.2024 |
| Abstrakt: | The canonical visual cycle employing RPE65 as the retinoid isomerase regenerates 11- cis -retinal to support both rod- and cone-mediated vision. Mutations of RPE65 are associated with Leber congenital amaurosis that results in rod and cone photoreceptor degeneration and vision loss of affected patients at an early age. Dark-reared Rpe65 -/- mouse has been known to form isorhodopsin that employs 9- cis -retinal as the photosensitive chromophore. The mechanism regulating 9- cis -retinal synthesis and the role of the endogenous 9- cis -retinal in cone survival and function remain largely unknown. In this study, we found that ablation of fatty acid transport protein-4 (FATP4), a negative regulator of 11- cis -retinol synthesis catalyzed by RPE65, increased the formation of 9- cis -retinal, but not 11- cis -retinal, in a light-independent mechanism in both sexes of RPE65-null rd 12 mice. Both rd 12 and rd 12; Fatp4 -/- mice contained a massive amount of all- trans -retinyl esters in the eyes, exhibiting 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 rd 12; Fatp4 -/ - mice were at least twofold greater than those in age-matched rd 12 mice. Moreover, FATP4 deficiency significantly shortened photopic b -wave implicit time, improved M-cone visual function, and substantially deaccelerated the progression of cone degeneration in rd 12 mice, whereas FATP4 deficiency in mice with wild-type Rpe65 alleles neither induced 9- cis -retinal formation nor influenced cone survival and function. These results identify FATP4 as a new regulator of synthesis of 9- cis -retinal, which is a "cone-tropic" chromophore supporting cone survival and function in the retinas with defective RPE65. Competing Interests: The authors declare no competing financial interests. (Copyright © 2024 the authors.) |
| Databáze: | MEDLINE |
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