Search

Inherited retinal dystrophies (IRD) are due to various gene mutations. Each mutated gene instigates a specific cell homeostasis disruption, leading to a modification in gene expression and retinal degeneration. We previously demonstrated that the polycomb-repressive complex-1 (PRC1) markedly contributes to the cell death process. To better understand these mechanisms, we herein study the role of PRC2, specifically EZH2, which often initiates the gene inhibition by PRC1. We observed that the epigenetic mark H3K27me3 generated by EZH2 was progressively and strongly expressed in some individual photoreceptors and that the H3K27me3-positive cell number increased before cell death. H3K27me3 accumulation occurs between early (accumulation of cGMP) and late (CDK4 expression) events of retinal degeneration. EZH2 hyperactivity was observed in four recessive and two dominant mouse models of retinal degeneration, as well as two dog models and one IRD patient. Acute pharmacological EZH2 inhibition by intravitreal injection decreased the appearance of H3K27me3 marks and the number of TUNEL-positive cells revealing that EZH2 contributes to the cell death process. Finally, we observed that the absence of the H3K27me3 mark is a biomarker of gene therapy treatment efficacy in XLRPA2 dog model. PRC2 and PRC1 are therefore important actors in the degenerative process of multiple forms of IRD.

We have identified and characterized a spontaneous Brown Norway from Janvier rat strain (BN-J) presenting a progressive retinal degeneration associated with early retinal telangiectasia, neuronal alterations, and loss of retinal Müller glial cells resembling human macular telangiectasia type 2 (MacTel 2), which is a retinal disease of unknown cause. Genetic analyses showed that the BN-J phenotype results from an autosomal recessive indel novel mutation in theCrb1gene, causing dislocalization of the protein from the retinal Müller glia (RMG)/photoreceptor cell junction. The transcriptomic analyses of primary RMG cultures allowed identification of the dysregulated pathways in BN-J rats compared with wild-type BN rats. Among those pathways, TGF-β and Kit Receptor Signaling, MAPK Cascade, Growth Factors and Inflammatory Pathways, G-Protein Signaling Pathways, Regulation of Actin Cytoskeleton, and Cardiovascular Signaling were found. Potential molecular targets linking RMG/photoreceptor interaction with the development of retinal telangiectasia are identified. This model can help us to better understand the physiopathologic mechanisms of MacTel 2 and other retinal diseases associated with telangiectasia.

Spectra of "white LEDs" are characterized by an intense emission in the blue region of the visible spectrum, absent in daylight spectra. This blue component and the high intensity of emission are the main sources of concern about the health risks of LEDs with respect to their toxicity to the eye and the retina. The aim of our study was to elucidate the role of blue light from LEDs in retinal damage. Commercially available white LEDs and four different blue LEDs (507, 473, 467, and 449nm) were used for exposure experiments on Wistar rats. Immunohistochemical stain, transmission electron microscopy, and Western blot were used to exam the retinas. We evaluated LED-induced retinal cell damage by studying oxidative stress, stress response pathways, and the identification of cell death pathways. LED light caused a state of suffering of the retina with oxidative damage and retinal injury. We observed a loss of photoreceptors and the activation of caspase-independent apoptosis, necroptosis, and necrosis. A wavelength dependence of the effects was observed. Phototoxicity of LEDs on the retina is characterized by a strong damage of photoreceptors and by the induction of necrosis.

The authors sought to determine the effect of genistein, a naturally occurring protein tyrosine kinase inhibitor, in a model of ischemia-reperfusion injury in the rat retina.Ischemia-reperfusion injury was induced by temporary optic nerve ligation. A dose of 0.034 mg, 0.34 mg, and 3.4 mg of genistein or dimethyl sulfoxide (DMSO) alone was injected intraperitoneally 1 hour before the ligation of the optic nerve and just after the start of reperfusion. After 48 hours of reperfusion, the effect of genistein on overall protein tyrosine phosphorylation in the retina was studied using Western blot analysis. After 168 hours, the effect of increasing doses of genistein on retinal degeneration was examined by quantitative morphometric analysis of histologic sections of the retina.The authors found that tyrosine phosphorylation was increased after 48 hours of reperfusion in the ischemia-reperfusion-injured eyes treated with DMSO alone. A severe inner retinal degeneration was observed in the animals treated with DMSO alone after 168 hours of reperfusion. The treatment with 3.4 mg genistein inhibited the increase in tyrosine phosphorylation and protected the eyes significantly from the induced ischemic retinal degeneration by morphometric analysis of the mean thickness of the inner limiting membrane to the outer limiting membrane, the inner plexiform layer, and the inner nuclear layer (P0.02). Treatments with lower amounts of genistein (0.034 mg and 0.34 mg) did not show a significant protection of retinal degeneration after the injury.Systemic administration of high dose of genistein, a dietary-derived isoflavone, can ameliorate an ischemia-reperfusion-induced retinal degeneration. Genistein may be useful to prevent neuronal degeneration in the inner retina as a result of ischemic injury.