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Ablation of Fatty Acid Transport Protein-4 Enhances Cone Survival, M-cone Vision, and Synthesis of Cone-Tropic 9-cis-Retinal in rd12 Mouse Model of Leber Congenital Amaurosis.
Li, Songhua; Jin, Minghao.
Afiliación
  • 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.
J Neurosci ; 44(27)2024 Jul 03.
Article en En | MEDLINE | ID: mdl-38811164
ABSTRACT
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 rd12 mice. Both rd12 and rd12;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 rd12;Fatp4-/ - mice were at least twofold greater than those in age-matched rd12 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 rd12 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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Células Fotorreceptoras Retinianas Conos / Proteínas de Transporte de Ácidos Grasos / Amaurosis Congénita de Leber Límite: Animals Idioma: En Revista: J Neurosci Año: 2024 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Células Fotorreceptoras Retinianas Conos / Proteínas de Transporte de Ácidos Grasos / Amaurosis Congénita de Leber Límite: Animals Idioma: En Revista: J Neurosci Año: 2024 Tipo del documento: Article