scholarly journals Importance of Autoimmune Responses in Progression of Retinal Degeneration Initiated by Gene Mutations

2021 ◽  
Vol 8 ◽  
Author(s):  
Grazyna Adamus
Keyword(s):  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Gene Mutations ◽  
Retinal Disease ◽  
Photoreceptor Cells ◽  
Site Effect ◽  
Gene Replacement ◽  
Genetic Mutation ◽  
Contributory Factor

Inherited retinal diseases (IRDs) are clinically and genetically heterogeneous rare disorders associated with retinal dysfunction and death of retinal photoreceptor cells, leading to blindness. Among the most frequent and severe forms of those retinopathies is retinitis pigmentosa (RP) that affects 1:4,000 individuals worldwide. The genes that have been implicated in RP are associated with the proteins present in photoreceptor cells or retinal pigment epithelium (RPE). Asymmetric presentation or sudden progression in retinal disease suggests that a gene mutation alone might not be responsible for retinal degeneration. Immune responses could directly target the retina or be site effect of immunity as a bystander deterioration. Autoantibodies against retinal autoantigens have been found in RP, which led to a hypothesis that autoimmunity could be responsible for the progression of photoreceptor cell death initiated by a genetic mutation. The other contributory factor to retinal degeneration is inflammation that activates the innate immune mechanisms, such as complement. If autoimmune responses contribute to the progression of retinopathy, this could have an implication on treatment, such as gene replacement therapy. In this review, we provide a perspective on the current role of autoimmunity/immunity in RP pathophysiology.

scholarly journals A Novel HDL-Mimetic Peptide HM-10/10 Protects RPE and Photoreceptors in Murine Models of Retinal Degeneration

2019 ◽  
Vol 20 (19) ◽  
pp. 4807 ◽  
Author(s):  
Feng Su ◽  
Christine Spee ◽  
Eduardo Araujo ◽  
Eric Barron ◽  
Mo Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Disease ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Mimetic Peptide ◽  
Age Related

Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. The retinal pigment epithelium (RPE) is a critical site of pathology in AMD. Oxidative stress plays a key role in the development of AMD. We generated a chimeric high-density lipoprotein (HDL), mimetic peptide named HM-10/10, with anti-oxidant properties and investigated its potential for the treatment of retinal disease using cell culture and animal models of RPE and photoreceptor (PR) degeneration. Treatment with HM-10/10 peptide prevented human fetal RPE cell death caused by tert-Butyl hydroperoxide (tBH)-induced oxidative stress and sodium iodate (NaIO3), which causes RPE atrophy and is a model of geographic atrophy in mice. We also show that HM-10/10 peptide ameliorated photoreceptor cell death and significantly improved retinal function in a mouse model of N-methyl-N-nitrosourea (MNU)-induced PR degeneration. Our results demonstrate that HM-10/10 protects RPE and retina from oxidant injury and can serve as a potential therapeutic agent for the treatment of retinal degeneration.

scholarly journals Forward genetic analysis using OCT screening identifiesSfxn3mutations leading to progressive outer retinal degeneration in mice

2020 ◽  
Vol 117 (23) ◽  
pp. 12931-12942 ◽  
Author(s):  
Bo Chen ◽  
Bogale Aredo ◽  
Yi Ding ◽  
Xin Zhong ◽  
Yuanfei Zhu ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Retinal Degeneration ◽  
Ganglion Cells ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Plexiform Layer ◽  
Retinal Disease ◽  
Forward Genetics ◽  
Unbiased Manner ◽  
Significant Gene

Retinal disease and loss of vision can result from any disruption of the complex pathways controlling retinal development and homeostasis. Forward genetics provides an excellent tool to find, in an unbiased manner, genes that are essential to these processes. UsingN-ethyl-N-nitrosourea mutagenesis in mice in combination with a screening protocol using optical coherence tomography (OCT) and automated meiotic mapping, we identified 11 mutations presumably causative of retinal phenotypes in genes previously known to be essential for retinal integrity. In addition, we found multiple statistically significant gene-phenotype associations that have not been reported previously and decided to target one of these genes,Sfxn3(encoding sideroflexin-3), using CRISPR/Cas9 technology. We demonstrate, using OCT, light microscopy, and electroretinography, that twoSfxn3−/−mouse lines developed progressive and severe outer retinal degeneration. Electron microscopy showed thinning of the retinal pigment epithelium and disruption of the external limiting membrane. Using single-cell RNA sequencing of retinal cells isolated from C57BL/6J mice, we demonstrate thatSfxn3is expressed in several bipolar cell subtypes, retinal ganglion cells, and some amacrine cell subtypes but not significantly in Müller cells or photoreceptors. In situ hybridization confirmed these findings. Furthermore, pathway analysis suggests that Sfxn3 may be associated with synaptic homeostasis. Importantly, electron microscopy analysis showed disruption of synapses and synaptic ribbons in the outer plexiform layer ofSfxn3−/−mice. Our work describes a previously unknown requirement forSfxn3in retinal function.

scholarly journals Loss of melanoregulin (MREG) enhances cathepsin-D secretion by the retinal pigment epithelium

2013 ◽  
Vol 30 (3) ◽  
pp. 55-64 ◽  
Author(s):  
LAURA S. FROST ◽  
VANDA S. LOPES ◽  
FRANK P. STEFANO ◽  
ALVINA BRAGIN ◽  
DAVID S. WILLIAMS ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Cathepsin D ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Disease ◽  
Protective Role ◽  
Phagocytic Cells ◽  
Phagocytic Capacity ◽  
Photoreceptor Outer Segments ◽  
Age Dependent

AbstractCathepsin-D (Cat-D) is a major proteolytic enzyme in phagocytic cells. In the retinal pigment epithelium (RPE), it is responsible for the daily degradation of photoreceptor outer segments (POSs) to maintain retinal homeostasis. Melanoregulin (MREG)-mediated loss of phagocytic capacity has been linked to diminished intracellular Cat-D activity. Here, we demonstrate that loss of MREG enhances the secretion of intermediate Cat-D (48 kDa), resulting in a net enhancement of extracellular Cat-D activity. These results suggest that MREG is required to maintain Cat-D homeostasis in the RPE and likely plays a protective role in retinal health. In this regard, in the Mregdsu/dsu mouse, we observe increased basal laminin. Loss of the Mregdsu allele is not lethal and therefore leads to slow age-dependent changes in the RPE. Thus, we propose that this model will allow us to study potential dysregulatory functions of Cat-D in retinal disease.

scholarly journals Potential Treatment of Retinal Diseases with Iron Chelators

2018 ◽  
Vol 11 (4) ◽  
pp. 112 ◽  
Author(s):  
Wanting Shu ◽  
Joshua Dunaief
Keyword(s):  
Retinal Degeneration ◽  
Therapeutic Potential ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Body ◽  
Age Related Macular Degeneration ◽  
Hereditary Diseases ◽  
Iron Chelators ◽  
Excess Iron ◽  
Age Related

Iron is essential for life, while excess iron can be toxic. Iron generates hydroxyl radical, which is the most reactive free radical, causing oxidative stress. Since iron is absorbed through the diet but not excreted from the body, it accumulates with age in tissues, including the retina, consequently leading to age-related toxicity. This accumulation is further promoted by inflammation. Hereditary diseases such as aceruloplasminemia, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, and posterior column ataxia with retinitis pigmentosa involve retinal degeneration associated with iron dysregulation. In addition to hereditary causes, dietary or parenteral iron supplementation has been recently reported to elevate iron levels in the retinal pigment epithelium (RPE) and promote retinal degeneration. Ocular siderosis from intraocular foreign bodies or subretinal hemorrhage can also lead to retinopathy. Evidence from mice and humans suggests that iron toxicity may contribute to age-related macular degeneration pathogenesis. Iron chelators can protect photoreceptors and RPE in various mouse models. The therapeutic potential for iron chelators is under investigation.

JAM-C maintains VEGR2 expression to promote retinal pigment epithelium cell survival under oxidative stress

2017 ◽  
Vol 117 (04) ◽  
pp. 750-757
Author(s):  
Xin Jia ◽  
Chen Zhao ◽  
Qishan Chen ◽  
Yuxiang Du ◽  
Lijuan Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Retinal Pigment Epithelium ◽  
Cell Survival ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelium Cell ◽  
Photoreceptor Cells ◽  
Rpe Cells

SummaryJunctional adhesion molecule-C (JAM-C) has been shown to play critical roles during development and in immune responses. However, its role in adult eyes under oxidative stress remains poorly understood. Here, we report that JAM-C is abundantly expressed in adult mouse retinae and choroids in vivo and in cultured retinal pigment epithelium (RPE) and photoreceptor cells in vitro. Importantly, both JAM-C expression and its membrane localisation are downregulated by H2O2-induced oxidative stress. Under H2O2-induced oxidative stress, JAM-C is critically required for the survival of human RPE cells. Indeed, loss of JAM-C by siRNA knockdown decreased RPE cell survival. Mechanistically, we show that JAM-C is required to maintain VEGFR2 expression in RPE cells, and VEGFR2 plays an important role in keeping the RPE cells viable since overexpression of VEGFR2 partially restored impaired RPE survival caused by JAM-C knockdown and increased RPE survival. We further show that JAM-C regulates VEGFR2 expression and, in turn, modulates p38 phosphorylation. Together, our data demonstrate that JAM-C plays an important role in maintaining VEGR2 expression to promote RPE cell survival under oxidative stress. Given the vital importance of RPE in the eye, approaches that can modulate JAM-C expression may have therapeutic values in treating diseases with impaired RPE survival.

scholarly journals PRDX6 Protects ARPE-19 Cells from Oxidative Damage via PI3K/AKT Signaling

2015 ◽  
Vol 36 (6) ◽  
pp. 2217-2228 ◽  
Author(s):  
Xu Zha ◽  
Guojiu Wu ◽  
Xueying Zhao ◽  
Liqiong Zhou ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Blue Light ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Annexin V ◽  
Retinal Disease ◽  
Akt Signaling ◽  
The Body ◽  
H2o2 Treatment

Background/Aims: Oxidative stress that damages cells of the retinal pigment epithelium (RPE) can cause the development of hereditary retinal disease (HRD). PRDX6, which is a member of the PRDX family, is essential for removing metabolic free radicals from the body. However, the effect of PRDX6 on oxidative stress in HRD remains unknown. In this study, we sought to investigate the role of PRDX6 in oxidative stress-induced HRD in ARPE-19 cells and the molecular mechanism involved. Methods: ARPE-19 cells were used in the current study. Intracellular ROS levels were determined by flow cytometry. Lipid peroxidation was measured using a commercial MDA assay kit. Cellular variability was determined by MTT assay. Apoptosis was determined using an Annexin V-FITC Apoptosis Detection Kit. mRNA and protein expression levels were detected by real-time PCR and western blot analysis, respectively. Results: We found that H2O2 and blue light could induce significant oxidative stress damage and cell death in ARPE-19 cells. Furthermore, we found that PRDX6 levels significantly decreased after H2O2 treatment. PRDX6 overexpression protected ARPE-19 cells from H2O2- and blue light-induced oxidative damage, while PRDX6 knockdown enhanced oxidative damage in these cells. Mechanistically, we found that PRDX6 prevented oxidative damage and promoted ARPE-19 cell survival through the PI3K/AKT signaling pathway. Conclusions: Collectively, these results suggest that PRDX6 protects ARPE-19 cells from H2O2-induced oxidative stress and apoptosis and that this protection is mediated at least partially through the PI3K/AKT pathway.

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