Age-related degeneration of the retinal pigment epithelium (RPE) of DJ-1 mice.

Abstract

Purpose : DJ-1 is ubiquitously expressed in many tissues including the brain where it functions as an antioxidant, redox-sensitive molecular chaperone and transcription regulator robustly protecting cells from oxidative stress. We previously reported mild structural and physiological changes including RPE thinning, central decrease in red/green cone opsin staining, decreased labeling of ezrin, broader distribution of ribeye labeling, decreased tyrosine hydroxylase in dopaminergic neurons, and increased DNA oxidation in the retinas of 3 and 6 month old DJ-1 knockout (KO) in comparison to control mice. The severity of these changes increased with age; therefore, in the present study we extended our analysis to older (18 month-old) mice and compared the results to young (3 month-old) DJ-1 KO and control mice.

Methods : The effects of DJ-1 deletion were examined in KO mice through non-invasive, fundus imaging in vivo using SLO and OCT. A profile analysis of the outer retina was performed from the four retinal quadrants to assess OCT signal reflectivity and lamina morphology. Photoreceptor and RPE function were assessed by ERG. Histological and immunohistological evaluation of the retinas of DJ-1 KO and control mice were also performed in cryosections as well as whole-mounted retina and RPE/choroid. Retina/RPE lysates were assayed for oxidation using antibodies.

Results : SLO showed no differences between the fundus of DJ-1 KO and control mice. OCT imaging demonstrated all retinal layers in both young and older DJ-1 KO retinas. The profile analysis revealed significant hyper-reflectivity of photoreceptor outer segments and outer retina thinning in DJ-1 KO in comparison to control mice for all retinal quadrants examined. ERG studies of older DJ-1 KO mice noted significant decreased values under dark- and light-adapted conditions. Histologically, changes in the RPE of the DJ-1 KO mice progressed from increased presence of vacuoles at 3 months of age to the presence of vacuoles and lesions at 18 months of age. The RPE lesions were also visible by OCT and in whole mounted RPE/choroid samples labeled with phalloidin. Photoreceptors were degenerated when opposing the RPE lesions. Increased protein carbonyl derivatives were detected in retina/RPE lysates from older DJ-1 KO mice.

Conclusions : DJ-1 KO mice display progressive signs of retinal/RPE degeneration in association with increased levels of oxidative stress markers.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.