In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell death.
RPE65 is a retinoid isomerase required for the production of 11-cis-retinal, the chromophore of both cone and rod visual pigments. We recently established an R91W knock-in mouse strain as homologous animal model for patients afflicted by this mutation in RPE65. These mice have impaired vision and can only synthesize minute amounts of 11-cis-retinal. Here, we investigated the consequences of this chromophore insufficiency on cone function and pathophysiology. We found that the R91W mutation caused cone opsin mislocalization and progressive geographic cone atrophy. Remnant visual function was mostly mediated by rods. Ablation of rod opsin corrected the localization of cone opsin and improved cone retinal function. Thus, our analyses indicate that under conditions of limited chromophore supply rods and cones compete for 11-cis-retinal that derives from regeneration pathway(s) which are reliant on RPE65. Due to their higher number and the instability of cone opsin, rods are privileged under this condition while cones suffer chromophore deficiency and degenerate. These findings reinforce the notion that in patients any effective gene therapy with RPE65 needs to target the cone-rich macula directly to locally restore the cones' chromophore supply outside the reach of rods.
Samardzija
Marijana
M
Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Zurich, Switzerland. marijana.samardzija@usz.uzh.ch
Tanimoto
Naoyuki
N
Kostic
Corinne
C
Beck
Susanne
S
Oberhauser
Vitus
V
Joly
Sandrine
S
Thiersch
Markus
M
Fahl
Edda
E
Arsenijevic
Yvan
Y
von Lintig
Johannes
J
Wenzel
Andreas
A
Seeliger
Mathias W
MW
Grimm
Christian
C
D019943:Amino Acid Substitution; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D016923:Cell Death; D055358:Cone Opsins / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D021381:Protein Transport; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology* / Q000378:metabolism*; D012168:Retinal Pigments / Q000378:metabolism*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism*; D012172:Retinaldehyde / Q000378:metabolism*; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
D002352:Carrier Proteins; D055358:Cone Opsins; D005136:Eye Proteins; D012168:Retinal Pigments; D012172:Retinaldehyde; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase