Abstract
Purpose :
Prolonged oxidative stress in the retinal pigment epithelium (RPE) can cause the death of RPE and photoreceptor cells, leading to vision loss in patients with dry-AMD. However, the molecular mechanism(s) of how oxidative stress in the RPE contributes to human retinal cell degeneration is poorly understood. The study aims to investigate the crosstalk between RPE and the retina while RPE is under prolonged oxidative stress.
Methods :
We used a mouse model of RPE oxidative stress (Sod2flox/flox/VMD2-cre mice), which were generated by RPE-specific deletion of Sod2, the mitochondrial isoform MnSoD, an oxidative stress response protein. These mice showed progressive retinal degeneration that recapitulates some of the features of dry AMD. To identify a possible mechanism for these pathologies, we harvested eyes from Sod2flox/flox/VMD2-cre mice and age-matched littermate control Sod2flox/flox mice and performed histological, biochemical, and visual function analysis.
Results :
Histological and electron microscopic analysis provided important information related to photoreceptor outer segments recycling, structure, and health, where progressive degeneration of the outer photoreceptor segments was observed. However, no changes in the expression of phototransduction proteins were detected. A modest increase in oxidative stress markers was noted. Oxidative stress in the RPE induced the expression of TFEB, one of the key transcription factors that determine the effective lysosomal clearance.
Conclusions :
This study establishes a connection between RPE oxidative stress and the induction of lysosomal biogenesis via TFEB. It has broad implications in understanding human inherited retinal degeneration and will help develop novel therapeutics to treat vision loss.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.