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Nature Reviews. Neuroscience Jul 2014Müller glia are the major glial component of the retina. They are one of the last retinal cell types to be born during development, and they function to maintain... (Review)
Review
Müller glia are the major glial component of the retina. They are one of the last retinal cell types to be born during development, and they function to maintain retinal homeostasis and integrity. In mammals, Müller glia respond to retinal injury in various ways that can be either protective or detrimental to retinal function. Although these cells can be coaxed to proliferate and generate neurons under special circumstances, these responses are meagre and insufficient for repairing a damaged retina. By contrast, in teleost fish (such as zebrafish), the response of Müller glia to retinal injury involves a reprogramming event that imparts retinal stem cell characteristics and enables them to produce a proliferating population of progenitors that can regenerate all major retinal cell types and restore vision. Recent studies have revealed several important mechanisms underlying Müller glial cell reprogramming and retina regeneration in fish that may lead to new strategies for stimulating retina regeneration in mammals.
Topics: Animals; Ependymoglial Cells; Humans; Nerve Net; Nerve Regeneration; Neuroglia; Retina; Signal Transduction
PubMed: 24894585
DOI: 10.1038/nrn3723 -
Progress in Retinal and Eye Research Jul 2021Diabetic retinopathy (DR) is a leading cause of blindness. It has long been regarded as vascular disease, but work in the past years has shown abnormalities also in the... (Review)
Review
Diabetic retinopathy (DR) is a leading cause of blindness. It has long been regarded as vascular disease, but work in the past years has shown abnormalities also in the neural retina. Unfortunately, research on the vascular and neural abnormalities have remained largely separate, instead of being integrated into a comprehensive view of DR that includes both the neural and vascular components. Recent evidence suggests that the most predominant neural cell in the retina (photoreceptors) and the adjacent retinal pigment epithelium (RPE) play an important role in the development of vascular lesions characteristic of DR. This review summarizes evidence that the outer retina is altered in diabetes, and that photoreceptors and RPE contribute to retinal vascular alterations in the early stages of the retinopathy. The possible molecular mechanisms by which cells of the outer retina might contribute to retinal vascular damage in diabetes also are discussed. Diabetes-induced alterations in the outer retina represent a novel therapeutic target to inhibit DR.
Topics: Diabetes Mellitus; Diabetic Retinopathy; Humans; Photoreceptor Cells; Retina; Retinal Pigment Epithelium
PubMed: 33188897
DOI: 10.1016/j.preteyeres.2020.100919 -
Molecules (Basel, Switzerland) Aug 2022Age-related macular degeneration (AMD) was described for the first time in the 1840s and is currently the leading cause of blindness for patients over 65 years in... (Review)
Review
Age-related macular degeneration (AMD) was described for the first time in the 1840s and is currently the leading cause of blindness for patients over 65 years in Western Countries. This disease impacts the eye's posterior segment and damages the macula, a retina section with high levels of photoreceptor cells and responsible for the central vision. Advanced AMD stages are divided into the atrophic (dry) form and the exudative (wet) form. Atrophic AMD consists in the progressive atrophy of the retinal pigment epithelium (RPE) and the outer retinal layers, while the exudative form results in the anarchic invasion by choroidal neo-vessels of RPE and the retina. This invasion is responsible for fluid accumulation in the intra/sub-retinal spaces and for a progressive dysfunction of the photoreceptor cells. To date, the few existing anti-AMD therapies may only delay or suspend its progression, without providing cure to patients. However, in the last decade, an outstanding number of research programs targeting its different aspects have been initiated by academics and industrials. This review aims to bring together the most recent advances and insights into the mechanisms underlying AMD pathogenicity and disease evolution, and to highlight the current hypotheses towards the development of new treatments, i.e., symptomatic vs. curative. The therapeutic options and drugs proposed to tackle these mechanisms are analyzed and critically compared. A particular emphasis has been given to the therapeutic agents currently tested in clinical trials, whose results have been carefully collected and discussed whenever possible.
Topics: Aged; Aging; Humans; Macular Degeneration; Photoreceptor Cells; Retina; Retinal Pigment Epithelium
PubMed: 36014339
DOI: 10.3390/molecules27165089 -
Progress in Retinal and Eye Research Sep 2023Mitochondrial function is key to support metabolism and homeostasis in the retina, an organ that has one of the highest metabolic rates body-wide and is constantly... (Review)
Review
Mitochondrial function is key to support metabolism and homeostasis in the retina, an organ that has one of the highest metabolic rates body-wide and is constantly exposed to photooxidative damage and external stressors. Mitophagy is the selective autophagic degradation of mitochondria within lysosomes, and can be triggered by distinct stimuli such as mitochondrial damage or hypoxia. Here, we review the importance of mitophagy in retinal physiology and pathology. In the developing retina, mitophagy is essential for metabolic reprogramming and differentiation of retina ganglion cells (RGCs). In basal conditions, mitophagy acts as a quality control mechanism, maintaining a healthy mitochondrial pool to meet cellular demands. We summarize the different autophagy- and mitophagy-deficient mouse models described in the literature, and discuss the potential role of mitophagy dysregulation in retinal diseases such as glaucoma, diabetic retinopathy, retinitis pigmentosa, and age-related macular degeneration. Finally, we provide an overview of methods used to monitor mitophagy in vitro, ex vivo, and in vivo. This review highlights the important role of mitophagy in sustaining visual function, and its potential as a putative therapeutic target for retinal and other diseases.
Topics: Mice; Animals; Mitophagy; Retina; Retinal Ganglion Cells; Autophagy; Mitochondria; Homeostasis
PubMed: 37454969
DOI: 10.1016/j.preteyeres.2023.101205 -
Cell Death and Differentiation Sep 2022Atrophic ("dry") form of age-related macular degeneration (AMD) is a leading cause of vision loss characterized by macular retinal pigment epithelium (RPE) and the...
Atrophic ("dry") form of age-related macular degeneration (AMD) is a leading cause of vision loss characterized by macular retinal pigment epithelium (RPE) and the ensuing photoreceptor degeneration. cGAS-STING signaling is a key cytosolic DNA sensor system in innate immunity and have recently been shown promotes RPE degeneration. However, expression regulation and therapeutic potential of cGAS and STING are not explored in retina under dry AMD pathogenic conditions. Our analysis shows upregulated STING RNA and increased chromatin accessibility around cGAS and STING promoters in macular retinas from dry AMD patients. cGAS-STING activation was detected in oxidative stress-induced mouse retina degeneration, accompanied with cytosolic leakage of damaged DNA in photoreceptors. Pharmaceutical or genetic approaches indicates STING promotes retina inflammation and degeneration upon oxidative damage. Drug screening reveals that BRD4 inhibitor JQ1 reduces cGAS-STING activation, inflammation and photoreceptor degeneration in the injured retina. BRD4 inhibition epigenetically suppresses STING transcription, and promotes autophagy-dependent cytosolic DNA clearance. Together, our results show that activation of cGAS-STING in retina may present pivotal innate immunity response in GA pathogenesis, whereas inhibition of cGAS-STING signaling by JQ1 could serve as a potential therapeutic strategy.
Topics: Animals; Inflammation; Membrane Proteins; Mice; Nuclear Proteins; Nucleotidyltransferases; Oxidative Stress; Retina; Retinal Pigment Epithelium; Transcription Factors
PubMed: 35347235
DOI: 10.1038/s41418-022-00967-4 -
The Journal of Biological Chemistry May 2023Dry age-related macular degeneration (AMD) and recessive Stargardt's disease (STGD1) lead to irreversible blindness in humans. The accumulation of all-trans-retinal...
Dry age-related macular degeneration (AMD) and recessive Stargardt's disease (STGD1) lead to irreversible blindness in humans. The accumulation of all-trans-retinal (atRAL) induced by chaos in visual cycle is closely associated with retinal atrophy in dry AMD and STGD1 but its critical downstream signaling molecules remain ambiguous. Here, we reported that activation of eukaryotic translation initiation factor 2α (eIF2α) by atRAL promoted retinal degeneration and photoreceptor loss through activating c-Jun N-terminal kinase (JNK) signaling-dependent apoptosis and gasdermin E (GSDME)-mediated pyroptosis. We determined that eIF2α activation by atRAL in photoreceptor cells resulted from endoplasmic reticulum homeostasis disruption caused at least in part by reactive oxygen species production, and it activated JNK signaling independent of and dependent on activating transcription factor 4 and the activating transcription factor 4/transcription factor C/EBP homologous protein (CHOP) axis. CHOP overexpression induced apoptosis of atRAL-loaded photoreceptor cells through activating JNK signaling rather than inhibiting the expression of antiapoptotic gene Bcl2. JNK activation by eIF2α facilitated photoreceptor cell apoptosis caused by atRAL via caspase-3 activation and DNA damage. Additionally, we demonstrated that eIF2α was activated in neural retina of light-exposed Abca4Rdh8 mice, a model that shows severe defects in atRAL clearance and displays primary features of human dry AMD and STGD1. Of note, inhibition of eIF2α activation by salubrinal effectively ameliorated retinal degeneration and photoreceptor apoptosis in Abca4Rdh8 mice upon light exposure. The results of this study suggest that eIF2α is an important target to develop drug therapies for the treatment of dry AMD and STGD1.
Topics: Animals; Humans; Mice; Activating Transcription Factor 4; Apoptosis; ATP-Binding Cassette Transporters; Photoreceptor Cells, Vertebrate; Retina; Retinal Degeneration; Retinal Pigment Epithelium; Retinaldehyde; Stargardt Disease; Eukaryotic Initiation Factor-2
PubMed: 37031820
DOI: 10.1016/j.jbc.2023.104686 -
Current Opinion in Genetics &... Oct 2016Unlike mammals, zebrafish are able to regenerate a damaged retina. Key to this regenerative response are Müller glia that respond to retinal injury by undergoing a... (Review)
Review
Unlike mammals, zebrafish are able to regenerate a damaged retina. Key to this regenerative response are Müller glia that respond to retinal injury by undergoing a reprogramming event that allows them to divide and generate a retinal progenitor that is multipotent and responsible for regenerating all major retinal neuron types. The fish and mammalian retina are composed of similar cell types with conserved function. Because of this it is anticipated that studies of retina regeneration in fish may suggest strategies for stimulating Müller glia reprogramming and retina regeneration in mammals. In this review we describe recent advances and future directions in retina regeneration research using zebrafish as a model system.
Topics: Animals; Animals, Genetically Modified; Cell Differentiation; Cell Proliferation; Humans; Nerve Regeneration; Neuroglia; Retina; Stem Cells; Zebrafish
PubMed: 27281280
DOI: 10.1016/j.gde.2016.05.009 -
FASEB Journal : Official Publication of... Nov 2019Blood-retinal barrier (BRB) breakdown is a typical event in the early stage of diabetic retinopathy (DR). This study aims to elucidate the protection of erianin, a...
Blood-retinal barrier (BRB) breakdown is a typical event in the early stage of diabetic retinopathy (DR). This study aims to elucidate the protection of erianin, a natural compound isolated from Lindl, against DR development. Erianin alleviated BRB breakdown and rescued the reduced claudin1 and occludin expression in retinas from streptozotocin-induced diabetic mice. Erianin reduced microglial activation, ERK1/2 phosphorylation, NF-κB transcriptional activation, and the elevated TNF-α expression both and . ERK1/2 inhibitor U0126 abrogated NF-κB activation in d-glucose-treated BV2 cells. Erianin reduced cellular glucose uptake, and molecular docking analysis indicated the potential interaction of erianin with glucose transporter (GLUT)1. GLUT1 inhibitor (STF31) reduced the activation of the ERK1/2-NF-κB signaling pathway. Coculture with d-glucose-stimulated microglial BV2 cells and with TNF-α stimulation both induced inner BRB and outer BRB damage in human retinal endothelial cells and APRE19 cells, but erianin improved all these damages. In summary, erianin attenuated BRB breakdown during DR development by inhibiting microglia-triggered retinal inflammation reducing cellular glucose uptake and abrogating the subsequent activation of the downstream ERK1/2-NF-κB pathway. Moreover, erianin also alleviated BRB damage induced by TNF-α released from the activated microglia.-Zhang, T., Ouyang, H., Mei, X., Lu, B., Yu, Z., Chen, K., Wang, Z., Ji, L. Erianin alleviates diabetic retinopathy by reducing retinal inflammation initiated by microglial cells inhibiting hyperglycemia-mediated ERK1/2-NF-κB signaling pathway.
Topics: Animals; Bibenzyls; Blood-Retinal Barrier; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Endothelial Cells; Hyperglycemia; Inflammation; MAP Kinase Signaling System; Male; Mice, Inbred C57BL; Microglia; NF-kappa B; Phenol; Retina
PubMed: 31365278
DOI: 10.1096/fj.201802614RRR -
CNS Neuroscience & Therapeutics Apr 2021Retinal disorders are leading causes of blindness and are due to an imbalance between reactive oxygen species and antioxidant scavenger (in favor of pro-oxidant species)... (Review)
Review
Retinal disorders are leading causes of blindness and are due to an imbalance between reactive oxygen species and antioxidant scavenger (in favor of pro-oxidant species) or a disruption of redox signaling and control. Indeed, it is well known that oxidative stress is one of the leading causes of retinal degenerative diseases. Different approaches using nutraceuticals resulted in protective effects in these disorders. This review will discuss the impact of oxidative stress in retinal neurodegenerative diseases and the potential strategies for avoiding or counteracting oxidative damage in retinal tissues, with a specific focus on taurine. Increasing data indicate that taurine may be effective in slowing down the progression of degenerative retinal diseases, thus suggesting that taurine can be a promising candidate for the prevention or as adjuvant treatment of these diseases. The mechanism by which taurine supplementation acts is mainly related to the reduction of oxidative stress. In particular, it has been demonstrated to improve retinal reduced glutathione, malondialdehyde, superoxide dismutase, and catalase activities. Antiapoptotic effects are also involved; however, the protective mechanisms exerted by taurine against retinal damage remain to be further investigated.
Topics: Animals; Humans; Oxidative Stress; Reactive Oxygen Species; Retina; Retinal Diseases; Taurine
PubMed: 33621439
DOI: 10.1111/cns.13610 -
Journal of Photochemistry and... Mar 2023Long-term light exposure, especially in the spectrum of blue light, frequently causes excessive oxidative stress in dry age-related macular degeneration (AMD). Here, to...
Long-term light exposure, especially in the spectrum of blue light, frequently causes excessive oxidative stress in dry age-related macular degeneration (AMD). Here, to gain insight into the underlying mechanism, we focused on mitochondrial dynamics alterations under long-term exposure to blue light in mouse and retinal cells. Six-month-old C57BL/6 mice were exposed to blue light (450 nm, 800 lx) for 2 weeks. The phenotypic changes in the retina were assayed using haematoxylin-eosin staining and transmission electron microscopy. Long-term blue light exposure significantly thinned each retinal layer in mice, induced retinal apoptosis and impaired retinal mitochondria. A retinal pigment epithelial cell line (ARPE-19) was used to verify the phototoxicity of blue light. Flow cytometry, immunofluorescence and MitoSox Red probe experiments confirmed that more total and mitochondria-specific ROS were generated in the blue light group than in the control group. Mito-Tracker Green probe showed fragmented mitochondrial morphology. The western blotting results indicated a significant increase in DRP1, OMA1, and BAX and a decrease in OPA1 and Bcl-2. In conclusion, long-term exposure to blue light damaged the retinas of mice, especially the ONL and RPE cells. There was destruction and dysfunction of mitochondria in RPE cells in vivo and in vitro. Mitochondrial dynamics were disrupted with characteristics of fusion-related obstruction after blue-light irradiation.
Topics: Mice; Animals; Retinal Degeneration; Reactive Oxygen Species; Mitochondrial Dynamics; Mice, Inbred C57BL; Retina; Oxidative Stress; Light; Retinal Pigment Epithelium
PubMed: 36724628
DOI: 10.1016/j.jphotobiol.2023.112654