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The Journal of Experimental Biology Dec 2021Melanopsin is a visual pigment that is expressed in a small subset of intrinsically photosensitive retinal ganglion cells (ipRGCs). It is involved in regulating... (Review)
Review
Melanopsin is a visual pigment that is expressed in a small subset of intrinsically photosensitive retinal ganglion cells (ipRGCs). It is involved in regulating non-image forming visual behaviors, such as circadian photoentrainment and the pupillary light reflex, while also playing a role in many aspects of image-forming vision, such as contrast sensitivity. Melanopsin was initially discovered in the melanophores of the skin of the frog Xenopus, and subsequently found in a subset of ganglion cells in rat, mouse and primate retinas. ipRGCs were initially thought to be a single retinal ganglion cell population, and melanopsin was thought to activate a single, invertebrate-like Gq/transient receptor potential canonical (TRPC)-based phototransduction cascade within these cells. However, in the 20 years since the discovery of melanopsin, our knowledge of this visual pigment and ipRGCs has expanded dramatically. Six ipRGC subtypes have now been identified in the mouse, each with unique morphological, physiological and functional properties. Multiple subtypes have also been identified in other species, suggesting that this cell type diversity is a general feature of the ipRGC system. This diversity has led to a renewed interest in melanopsin phototransduction that may not follow the canonical Gq/TRPC cascade in the mouse or in the plethora of other organisms that express the melanopsin photopigment. In this Review, we discuss recent findings and discoveries that have challenged the prevailing view of melanopsin phototransduction as a single pathway that influences solely non-image forming functions.
Topics: Animals; Light Signal Transduction; Mice; Rats; Retina; Retinal Ganglion Cells; Rod Opsins
PubMed: 34842918
DOI: 10.1242/jeb.226522 -
The Journal of Experimental Medicine Dec 2023Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases, such as age-related macular degeneration....
Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases, such as age-related macular degeneration. In-depth characterization of RPE cell product identity and critical quality attributes are needed to enhance efficacy and safety of replacement therapy strategies. Here, we characterized an adult RPE stem cell-derived (RPESC-RPE) cell product using bulk and single-cell RNA sequencing (scRNA-seq), assessing functional cell integration in vitro into a mature RPE monolayer and in vivo efficacy by vision rescue in the Royal College of Surgeons rats. scRNA-seq revealed several distinct subpopulations in the RPESC-RPE product, some with progenitor markers. We identified RPE clusters expressing genes associated with in vivo efficacy and increased cell integration capability. Gene expression analysis revealed lncRNA (TREX) as a predictive marker of in vivo efficacy. TREX knockdown decreased cell integration while overexpression increased integration in vitro and improved vision rescue in the RCS rats.
Topics: Animals; Rats; Biomarkers; Gene Expression Profiling; Neurons; Epithelial Cells; Retinal Pigments
PubMed: 37728563
DOI: 10.1084/jem.20230913 -
Biomolecules May 2023Age-related macular degeneration (AMD) causes vision loss in the elderly population. Dry AMD leads to the formation of Drusen, while wet AMD is characterized by cell... (Review)
Review
Age-related macular degeneration (AMD) causes vision loss in the elderly population. Dry AMD leads to the formation of Drusen, while wet AMD is characterized by cell proliferation and choroidal angiogenesis. The retinal pigment epithelium (RPE) plays a key role in AMD pathogenesis. In particular, helioreceptor renewal depends on outer segment phagocytosis of RPE cells, while RPE autophagy can protect cells from oxidative stress damage. However, when the oxidative stress burden is too high and homeostasis is disturbed, the phagocytosis and autophagy functions of RPE become damaged, leading to AMD development and progression. Hence, characterizing the roles of RPE cell phagocytosis and autophagy in the pathogenesis of AMD can inform the development of potential therapeutic targets to prevent irreversible RPE and photoreceptor cell death, thus protecting against AMD.
Topics: Aged; Humans; Phagocytosis; Autophagy; Macular Degeneration; Oxidative Stress; Epithelial Cells; Retinal Pigments
PubMed: 37371481
DOI: 10.3390/biom13060901 -
Photochemical & Photobiological... Nov 2015Rhodopsin has been intensively characterized in its role as a visual pigment and G protein-coupled receptor responsible for dim-light vision. We recently discovered that... (Review)
Review
Rhodopsin has been intensively characterized in its role as a visual pigment and G protein-coupled receptor responsible for dim-light vision. We recently discovered that it also functions as an ATP-independent phospholipid scramblase: when reconstituted into large unilamellar vesicles, rhodopsin accelerates the normally sluggish transbilayer translocation of common phospholipids by more than 1000-fold, to rates in excess of 10 000 phospholipids transported per rhodopsin per second. Here we summarize the work leading to this discovery and speculate on the mechanism by which rhodopsin scrambles phospholipids. We also present a hypothesis that rhodopsin's scramblase activity is necessary for the function of the ABC transporter ABCA4 that is responsible for mitigating the toxic accumulation of 11-cis-retinal and bis-retinoids in the retina.
Topics: Animals; Humans; Phospholipids; Rhodopsin
PubMed: 26179029
DOI: 10.1039/c5pp00195a -
Disease Models & Mechanisms Jul 2023Oxidative stress has been implicated in the pathogenesis of age-related macular degeneration, the leading cause of blindness in older adults, with retinal pigment...
Oxidative stress has been implicated in the pathogenesis of age-related macular degeneration, the leading cause of blindness in older adults, with retinal pigment epithelium (RPE) cells playing a key role. To better understand the cytotoxic mechanisms underlying oxidative stress, we used cell culture and mouse models of iron overload, as iron can catalyze reactive oxygen species formation in the RPE. Iron-loading of cultured induced pluripotent stem cell-derived RPE cells increased lysosomal abundance, impaired proteolysis and reduced the activity of a subset of lysosomal enzymes, including lysosomal acid lipase (LIPA) and acid sphingomyelinase (SMPD1). In a liver-specific Hepc (Hamp) knockout murine model of systemic iron overload, RPE cells accumulated lipid peroxidation adducts and lysosomes, developed progressive hypertrophy and underwent cell death. Proteomic and lipidomic analyses revealed accumulation of lysosomal proteins, ceramide biosynthetic enzymes and ceramides. The proteolytic enzyme cathepsin D (CTSD) had impaired maturation. A large proportion of lysosomes were galectin-3 (Lgals3) positive, suggesting cytotoxic lysosomal membrane permeabilization. Collectively, these results demonstrate that iron overload induces lysosomal accumulation and impairs lysosomal function, likely due to iron-induced lipid peroxides that can inhibit lysosomal enzymes.
Topics: Mice; Animals; Proteomics; Oxidative Stress; Lysosomes; Iron; Iron Overload; Epithelial Cells; Retinal Pigments; Retinal Pigment Epithelium
PubMed: 37401371
DOI: 10.1242/dmm.050066 -
Redox Biology Aug 2023Diabetic retinopathy (DR) is a major cause of blindness in adult, and the accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR....
Metformin inhibits methylglyoxal-induced retinal pigment epithelial cell death and retinopathy via AMPK-dependent mechanisms: Reversing mitochondrial dysfunction and upregulating glyoxalase 1.
Diabetic retinopathy (DR) is a major cause of blindness in adult, and the accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is a precursor of AGEs. Although the therapeutic potential of metformin for retinopathy disorders has recently been elucidated, possibly through AMPK activation, it remains unknown how metformin directly affects the MGO-induced stress response in retinal pigment epithelial cells. Therefore, in this study, we compared the effects of metformin and the AMPK activator A769662 on MGO-induced DR in mice, as well as evaluated cytotoxicity, mitochondrial dynamic changes and dysfunction in ARPE-19 cells. We found MGO can induce mitochondrial ROS production and mitochondrial membrane potential loss, but reduce cytosolic ROS level in ARPE-19 cells. Although these effects of MGO can be reversed by both metformin and A769662, we demonstrated that reduction of mitochondrial ROS production rather than restoration of cytosolic ROS level contributes to cell protective effects of metformin and A769662. Moreover, MGO inhibits AMPK activity, reduces LC3II accumulation, and suppresses protein and gene expressions of MFN1, PGC-1α and TFAM, leading to mitochondrial fission, inhibition of mitochondrial biogenesis and autophagy. In contrast, these events of MGO were reversed by metformin in an AMPK-dependent manner as evidenced by the effects of compound C and AMPK silencing. In addition, we observed an AMPK-dependent upregulation of glyoxalase 1, a ubiquitous cellular enzyme that participates in the detoxification of MGO. In intravitreal drug-treated mice, we found that AMPK activators can reverse the MGO-induced cotton wool spots, macular edema and retinal damage. Functional, histological and optical coherence tomography analysis support the protective actions of both agents against MGO-elicited retinal damage. Metformin and A769662 via AMPK activation exert a strong protection against MGO-induced retinal pigment epithelial cell death and retinopathy. Therefore, metformin and AMPK activator can be therapeutic agents for DR.
Topics: Mice; Animals; Metformin; AMP-Activated Protein Kinases; Pyruvaldehyde; Reactive Oxygen Species; Magnesium Oxide; Lactoylglutathione Lyase; Mitochondria; Retinal Diseases; Glycation End Products, Advanced; Epithelial Cells; Retinal Pigments
PubMed: 37348156
DOI: 10.1016/j.redox.2023.102786 -
Cell Reports Aug 2023In daylight, demand for visual chromophore (11-cis-retinal) exceeds supply by the classical visual cycle. This shortfall is compensated, in part, by the retinal...
In daylight, demand for visual chromophore (11-cis-retinal) exceeds supply by the classical visual cycle. This shortfall is compensated, in part, by the retinal G-protein-coupled receptor (RGR) photoisomerase, which is expressed in both the retinal pigment epithelium (RPE) and in Müller cells. The relative contributions of these two cellular pools of RGR to the maintenance of photoreceptor light responses are not known. Here, we use a cell-specific gene reactivation approach to elucidate the kinetics of RGR-mediated recovery of photoreceptor responses following light exposure. Electroretinographic measurements in mice with RGR expression limited to either cell type reveal that the RPE and a specialized subset of Müller glia contribute both to scotopic and photopic function. We demonstrate that 11-cis-retinal formed through photoisomerization is rapidly hydrolyzed, consistent with its role in a rapid visual pigment regeneration process. Our study shows that RGR provides a pan-retinal sink for all-trans-retinal released under sustained light conditions and supports rapid chromophore regeneration through the photic visual cycle.
Topics: Animals; Mice; Retinal Pigment Epithelium; Retinaldehyde; Retinal Pigments; Receptors, G-Protein-Coupled; Neuroglia; Retinal Cone Photoreceptor Cells
PubMed: 37585292
DOI: 10.1016/j.celrep.2023.112982 -
Trends in Neurosciences Jan 2022MicroRNAs are short, evolutionarily conserved noncoding RNAs that are critical for the control of normal cellular physiology. In the retina, photoreceptors are highly... (Review)
Review
MicroRNAs are short, evolutionarily conserved noncoding RNAs that are critical for the control of normal cellular physiology. In the retina, photoreceptors are highly specialized neurons that transduce light into electrical signals. Photoreceptors, however, are unable to process visual stimuli without the support of the retinal pigment epithelium (RPE). The RPE performs numerous functions to aid the retina, including the generation of visual chromophore and metabolic support. Recent work has underscored how microRNAs enable vision through their contributions to RPE functions. This review focuses on the biogenesis and control of microRNAs in rodents and humans, the roles microRNAs play in RPE function and degeneration, and how microRNAs could serve as potential therapeutics and biomarkers for visual diseases.
Topics: Humans; MicroRNAs; Retina; Retinal Pigment Epithelium; Retinal Pigments; Vision, Ocular
PubMed: 34753606
DOI: 10.1016/j.tins.2021.10.008 -
Neurosciences (Riyadh, Saudi Arabia) Oct 2014Vision is perhaps the most important of all our senses, and gives us an immense amount of information regarding the outside world. The initial format in which this... (Review)
Review
Vision is perhaps the most important of all our senses, and gives us an immense amount of information regarding the outside world. The initial format in which this information reaches the retina are photons; particles of energy radiation of a given wavelength emitted or reflected from our surroundings. The brain itself however, perceives information in electrical signals via action potentials and changes in electrochemical gradients. The processes involved in the transduction of photons into electrical potentials will be the focus of this article. This review article summarizes the recent advances in understanding these complex pathways and provides an overview of the main molecules involved in the neurobiology of vision.
Topics: Action Potentials; Animals; Calcium Signaling; Cyclic GMP; G-Protein-Coupled Receptor Kinase 1; Humans; Opsins; Photons; Protein Conformation; Recoverin; Retina; Retinal Pigments; Retinal Rod Photoreceptor Cells; Retinaldehyde; Second Messenger Systems; Vision, Ocular
PubMed: 25274585
DOI: No ID Found -
Retina (Philadelphia, Pa.) Nov 2023To describe specific clinical, multimodal imaging, and natural history features of an unusual variant of acute zonal occult outer retinopathy. (Observational Study)
Observational Study
PURPOSE
To describe specific clinical, multimodal imaging, and natural history features of an unusual variant of acute zonal occult outer retinopathy.
METHODS
Retrospective, observational, longitudinal, multicenter case series. Patients exhibiting this unusual clinical condition among cases previously diagnosed with acute zonal occult outer retinopathy were included. Multimodal imaging, laboratory evaluations, and genetic testing for inherited retinal diseases were reviewed.
RESULTS
Twenty eyes from 10 patients (8 females and 2 males) with a mean age of 54.1 ± 13.3 years (range, 38-71 years) were included. The mean follow-up duration was 13.1 ± 5.3 years (range, 8-23 years). Presenting symptoms were bilateral in 7 patients (85% of eyes) and included scotomata and photopsia. All patients had bilateral lesions at presentation involving the peripapillary and far peripheral retina. Baseline optical coherence tomography showed alteration of the retinal pigment epithelium and photoreceptor layers corresponding to zonal areas of fundus autofluorescence abnormalities. Centrifugal and centripetal progression of the peripapillary and far-peripheral lesions, respectively, occurred over the follow-up, resulting in areas of complete outer retinal and retinal pigment epithelium atrophy.
CONCLUSION
Initial alteration of photoreceptors and retinal pigment epithelium and a stereotypical natural course that includes involvement of the far retinal periphery, characterize this unusual condition. It may represent a variant of acute zonal occult outer retinopathy or may be a new entity. We suggest to call it multizonal outer retinopathy and retinal pigment epitheliopathy .
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Fluorescein Angiography; Retinal Diseases; Retinal Pigments; Retrospective Studies; Scotoma; Tomography, Optical Coherence; Visual Fields
PubMed: 37748093
DOI: 10.1097/IAE.0000000000003927