Abstract
The eye is continuously under oxidative stress due to high metabolic activity and reactive oxygen species generated by daily light exposure. The redox-sensitive protein DJ-1 has proven to be essential in order to protect retina and retinal pigment epithelium (RPE) from oxidative-stress-induced degeneration. Here, we analyzed the specific role of Müller cell DJ-1 in the adult zebrafish retina by re-establishing Müller-cell-specific DJ-1 expression in a DJ-1 knockout retina. Loss of DJ-1 resulted in an age-dependent retinal degeneration, including loss of cells in the ganglion cell layer, retinal thinning, photoreceptor disorganization and RPE cell dysfunction. The degenerative phenotype induced by the absence of DJ-1 was inhibited by solely expressing DJ-1 in Müller cells. The protective effect was dependent upon the cysteine-106 residue of DJ-1, which has been shown to be an oxidative sensor of DJ-1. In a label-free proteomics analysis of isolated retinas, we identified proteins differentially expressed after DJ-1 knockout, but with restored levels after Müller cell DJ-1 re-insertion. Our data show that Müller cell DJ-1 has a major role in protecting the retina from age-dependent oxidative stress.
Highlights
IntroductionDJ-1 is a multifunctional and ubiquitously expressed protein encoded by the park gene [1]
We have reinserted DJ-1 and DJ-1c106a in glia cells of the knockout line, using ISce1-transgenesis and elements of the glia fibrillary acidic protein promotor to enable glial specific expression of DJ-1. This glial expression is restricted to the Müller cells [20,30], making it possible to study the effect of Müller specific DJ-1 expression in a retinal DJ-1 null background
We show that loss of DJ-1 in zebrafish induces an age-related retinal degeneration similar to what has been observed in DJ-1-deficient mice [46] and to retinal pathologies associated with neurodegenerative diseases [47]
Summary
DJ-1 is a multifunctional and ubiquitously expressed protein encoded by the park gene [1]. It is highly recognized as a general protector of oxidative stress through regulating antioxidant and anti-apoptotic gene transcription, as well as several distinct pro-survival pathways [2,3]. RPE cells have an important role in diurnal phagocytosis of photoreceptors, as distal. RPE cells have an important role in diurnal phagocytosis of photoreceptors, as distal ends ends of of their their outer outer segments segments are are pinched pinched off off and and phagocytosed phagocytosed by by neighboring neighboring RPE.
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