Chromophore supply modulates cone function and survival in retinitis pigmentosa mouse models. Proc Natl Acad Sci U S A. 2023;120(23):e2217885120.
JMG, Mice, Animals, Retina, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Retinitis Pigmentosa, Color Vision, Disease Models, Animal
Proc Natl Acad Sci U S A. 2023;120(23):e2217885120.
This work was funded by Howard Hughes Medical Institute (to C.L.C.), NIH grants K99EY030951 (to Y.X. before June 30, 2022), Lingang Laboratory startup fund (to Y.X. after July 20, 2022), and R01EY030912 (to V.J.K.). We acknowledge support from NIH grant P30EY034070 and from an unrestricted grant from Research to Prevent Blindness (to the Gavin Herbert Eye Institute at the University of California, Irvine). G.B.C. was supported by NIH grant R01HD036878.
Retinitis pigmentosa (RP) is an ocular disease characterized by the loss of night vision, followed by the loss of daylight vision. Daylight vision is initiated in the retina by cone photoreceptors, which are gradually lost in RP, often as bystanders in a disease process that initiates in their neighboring rod photoreceptors. Using physiological assays, we investigated the timing of cone electroretinogram (ERG) decline in RP mouse models. A correlation between the time of loss of the cone ERG and the loss of rods was found. To investigate a potential role of the visual chromophore supply in this loss, mouse mutants with alterations in the regeneration of the retinal chromophore, 11-cis retinal, were exam- ined. Reducing chromophore supply via mutations in Rlbp1 or Rpe65 resulted in greater cone function and survival in a RP mouse model. Conversely, overexpression of Rpe65 and Lrat, genes that can drive the regeneration of the chromophore, led to greater cone degeneration. These data suggest that abnormally high chromophore supply to cones upon the loss of rods is toxic to cones, and that a potential therapy in at least some forms of RP is to slow the turnover and/or reduce the level of visual chromophore in the retina.