The Rpe65 Leu450Met variation increases retinal resistance against light-induced degeneration by slowing rhodopsin regeneration.
Excessive light can cause retinal degeneration and may be an environmental cofactor accelerating retinal dystrophies and age-related diseases. In rodent models, the light damage susceptibility (LDS) of the retina is determined genetically. In two mouse strains, with different degrees of LDS, a Leu450Met variation in the pigment epithelial protein RPE65 was shown recently to cosegregate with low LDS. Because light damage is rhodopsin-mediated, and RPE65 is essential for the regeneration of rhodopsin in the visual cycle, we analyzed this variation regarding rhodopsin metabolism and LDS in four mouse strains. We found that, in contrast to previous assertions, LDS does not correlate with the maximal retinal content of rhodopsin present after dark adaptation. Instead, LDS correlated positively with the kinetics of rhodopsin regeneration, which determine rhodopsin availability during light exposure. Light damage occurred after absorption of a threshold dose of photons and thus fast regeneration, as observed in those two strains having Leu at position 450 of RPE65, was correlated with the occurrence of photoreceptor apoptosis after short exposure. In contrast, mice with the Leu450Met variation of Rpe65 regenerated rhodopsin with slow kinetics and showed an increased resistance to light-induced retinal degeneration. In these mice, RPE65 protein levels were reduced by a post-transcriptional mechanism. F(1) hybrid mice, carrying one normal and one variant Rpe65 gene, had intermediate levels of the corresponding protein and showed intermediate rhodopsin regeneration kinetics and an intermediate LDS. Thus, none of the two variants of Rpe65 had a dominant effect.
Wenzel
A
A
Laboratory of Retinal Cell Biology, Department of Ophthalmology, University Hospital Zürich, CH-8091 Zürich, Switzerland.
Reme
C E
CE
Williams
T P
TP
Hafezi
F
F
Grimm
C
C
D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D002352:Carrier Proteins; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D005136:Eye Proteins; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D008027:Light / Q000009:adverse effects*; D051379:Mice; D008815:Mice, Inbred Strains; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D011506:Proteins / Q000235:genetics*; D012160:Retina / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D012162:Retinal Degeneration / Q000378:metabolism* / Q000473:pathology; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism*; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
D002352:Carrier Proteins; D005136:Eye Proteins; D011506:Proteins; D012243:Rhodopsin; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase