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Annual Review of Vision Science Sep 2021Our sense of sight relies on photoreceptors, which transduce photons into the nervous system's electrochemical interpretation of the visual world. These precious... (Review)
Review
Our sense of sight relies on photoreceptors, which transduce photons into the nervous system's electrochemical interpretation of the visual world. These precious photoreceptors can be disrupted by disease, injury, and aging. Once photoreceptors start to die, but before blindness occurs, the remaining retinal circuitry can withstand, mask, or exacerbate the photoreceptor deficit and potentially be receptive to newfound therapies for vision restoration. To maximize the retina's receptivity to therapy, one must understand the conditions that influence the state of the remaining retina. In this review, we provide an overview of the retina's structure and function in health and disease. We analyze a collection of observations on photoreceptor disruption and generate a predictive model to identify parameters that influence the retina's response. Finally, we speculate on whether the retina, with its remarkable capacity to function over light levels spanning nine orders of magnitude, uses these same adaptational mechanisms to withstand and perhaps mask photoreceptor loss.
Topics: Photoreceptor Cells; Retina
PubMed: 34524879
DOI: 10.1146/annurev-vision-100119-124713 -
Journal of Lipid Research 2021Photoreceptors have high energy demands and a high density of mitochondria that produce ATP through oxidative phosphorylation (OXPHOS) of fuel substrates. Although... (Review)
Review
Photoreceptors have high energy demands and a high density of mitochondria that produce ATP through oxidative phosphorylation (OXPHOS) of fuel substrates. Although glucose is the major fuel for CNS brain neurons, in photoreceptors (also CNS), most glucose is not metabolized through OXPHOS but is instead metabolized into lactate by aerobic glycolysis. The major fuel sources for photoreceptor mitochondria remained unclear for almost six decades. Similar to other tissues (like heart and skeletal muscle) with high metabolic rates, photoreceptors were recently found to metabolize fatty acids (palmitate) through OXPHOS. Disruption of lipid entry into photoreceptors leads to extracellular lipid accumulation, suppressed glucose transporter expression, and a duel lipid/glucose fuel shortage. Modulation of lipid metabolism helps restore photoreceptor function. However, further elucidation of the types of lipids used as retinal energy sources, the metabolic interaction with other fuel pathways, as well as the cross-talk among retinal cells to provide energy to photoreceptors is not fully understood. In this review, we will focus on the current understanding of photoreceptor energy demand and sources, and potential future investigations of photoreceptor metabolism.
Topics: Photoreceptor Cells
PubMed: 32094231
DOI: 10.1194/jlr.TR120000618 -
The Journal of Membrane Biology Oct 2019Rhodopsin is the light receptor in photoreceptor cells of the retina and a prototypical G protein-coupled receptor. Two types of quaternary structures can be adopted by... (Review)
Review
Rhodopsin is the light receptor in photoreceptor cells of the retina and a prototypical G protein-coupled receptor. Two types of quaternary structures can be adopted by rhodopsin. If rhodopsin folds and attains a proper tertiary structure, it can then form oligomers and nanodomains within the photoreceptor cell membrane. In contrast, if rhodopsin misfolds, it cannot progress through the biosynthetic pathway and instead will form aggregates that can cause retinal degenerative disease. In this review, emerging views are highlighted on the supramolecular organization of rhodopsin within the membrane of photoreceptor cells and the aggregation of rhodopsin that can lead to retinal degeneration.
Topics: Animals; Cell Membrane; Humans; Photoreceptor Cells, Vertebrate; Protein Domains; Protein Folding; Retinal Degeneration; Rhodopsin
PubMed: 31286171
DOI: 10.1007/s00232-019-00078-1 -
Trends in Cell Biology Nov 2020The light-sensitive outer segment organelle of the vertebrate photoreceptor cell is a modified cilium filled with hundreds of flattened 'disc' membranes that provide... (Review)
Review
The light-sensitive outer segment organelle of the vertebrate photoreceptor cell is a modified cilium filled with hundreds of flattened 'disc' membranes that provide vast light-absorbing surfaces. The outer segment is constantly renewed with new discs added at its base every day. This continuous process is essential for photoreceptor viability. In this review, we describe recent breakthroughs in the understanding of disc morphogenesis, with a focus on the molecular mechanisms responsible for initiating disc formation from the ciliary membrane. We highlight the discoveries that this mechanism evolved from an innate ciliary process of releasing small extracellular vesicles, or ectosomes, and that both disc formation and ectosome release rely on the actin cytoskeleton.
Topics: Actins; Animals; Cell-Derived Microparticles; Cilia; Humans; Models, Biological; Photoreceptor Cells; Polymerization
PubMed: 32900570
DOI: 10.1016/j.tcb.2020.08.005 -
Advances in Experimental Medicine and... 2023The cone-rod homeobox (CRX) protein is a key transcription factor essential for photoreceptor function and survival. Mutations in human CRX gene are linked to a wide... (Review)
Review
The cone-rod homeobox (CRX) protein is a key transcription factor essential for photoreceptor function and survival. Mutations in human CRX gene are linked to a wide spectrum of blinding diseases ranging from mild macular dystrophy to severe Leber congenital amaurosis (LCA), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). These diseases are still incurable and mostly inherited in an autosomal dominant form. Dysfunctional mutant CRX protein interferes with the function of wild-type CRX protein, demonstrating the dominant negative effect. At present, gene augmentation is the most promising treatment strategy for hereditary diseases. This study aims to review the pathogenic mechanisms of various CRX mutations and propose two therapeutic strategies to rescue sick photoreceptors in CRX-associated retinopathies, namely, Tet-On-hCRX system and adeno-associated virus (AAV)-mediated gene augmentation. The outcome of proposed studies will guide future translational research and suggest guidelines for therapy evaluation in terms of treatment safety and efficacy.
Topics: Humans; Leber Congenital Amaurosis; Mutation; Photoreceptor Cells; Retinal Diseases; Retinitis Pigmentosa
PubMed: 37440026
DOI: 10.1007/978-3-031-27681-1_21 -
International Journal of Molecular... May 2021Retinoprotective proteins play important roles for retinal tissue integrity. They can directly affect the function and the survival of photoreceptors, and/or indirectly... (Review)
Review
Retinoprotective proteins play important roles for retinal tissue integrity. They can directly affect the function and the survival of photoreceptors, and/or indirectly target the retinal pigment epithelium (RPE) and endothelial cells that support these tissues. Retinoprotective proteins are used in basic, translational and in clinical studies to prevent and treat human retinal degenerative disorders. In this review, we provide an overview of proteins that protect the retina and focus on pigment epithelium-derived factor (PEDF), and its effects on photoreceptors, RPE cells, and endothelial cells. We also discuss delivery systems such as pharmacologic and genetic administration of proteins to achieve photoreceptor survival and retinal tissue integrity.
Topics: Animals; Endothelial Cells; Eye Proteins; Humans; Nerve Growth Factors; Photoreceptor Cells; Photoreceptor Cells, Vertebrate; Protein Transport; Retina; Retinal Degeneration; Retinal Neurons; Retinal Pigment Epithelium; Serpins
PubMed: 34069505
DOI: 10.3390/ijms22105344 -
Genes Sep 2020Retinitis pigmentosa (RP) is the most common cause of inherited blindness and is characterised by the progressive loss of retinal photoreceptors. However, RP is a highly... (Review)
Review
Retinitis pigmentosa (RP) is the most common cause of inherited blindness and is characterised by the progressive loss of retinal photoreceptors. However, RP is a highly heterogeneous disease and, while much progress has been made in developing gene replacement and gene editing treatments for RP, it is also necessary to develop treatments that are applicable to all causative mutations. Further understanding of the mechanisms leading to photoreceptor death is essential for the development of these treatments. Recent work has therefore focused on the role of apoptotic and non-apoptotic cell death pathways in RP and the various mechanisms that trigger these pathways in degenerating photoreceptors. In particular, several recent studies have begun to elucidate the role of microglia and innate immune response in the progression of RP. Here, we discuss some of the recent progress in understanding mechanisms of rod and cone photoreceptor death in RP and summarise recent clinical trials targeting these pathways.
Topics: Animals; Apoptosis; Humans; Photoreceptor Cells, Vertebrate; Retinitis Pigmentosa
PubMed: 32987769
DOI: 10.3390/genes11101120 -
Molecular Vision 2021To describe the derivation of photoreceptor precursor cells from human embryonic stem cells by coculture with RPE cells.
PURPOSE
To describe the derivation of photoreceptor precursor cells from human embryonic stem cells by coculture with RPE cells.
METHODS
Human embryonic stem cells were induced to differentiate into neural precursor cells and then cocultured with RPE cells to obtain cells showing retinal photoreceptor features. Immunofluorescent staining, reverse transcription-PCR (RT-PCR), and microarray analysis were performed to identify photoreceptor markers, and a cGMP assay was used for in vitro functional analysis. After subretinal injection in rat animal models, retinal function was determined with electroretinography and optokinetic response detection, and immunofluorescent staining was performed to assess the survival of the injected cells.
RESULTS
Cocultured cells were positive for rhodopsin, red and blue opsin, recoverin, and phosphodiesterase 6 beta on immunofluorescent staining and RT-PCR. Serial detection of stem cell-, neural precursor-, and photoreceptor-specific markers was noted in each stage of differentiation with microarray analysis. Increased cGMP hydrolysis in light-exposed conditions compared to that in dark conditions was observed. After the subretinal injection in the rats, preservation of optokinetic responses was noted up to 20 weeks, while electroretinographic response decreased. Survival of the injected cells was confirmed with positive immunofluorescence staining of human markers at 8 weeks.
CONCLUSIONS
Cells showed photoreceptor-specific features when stem cell-derived neurogenic precursors were cocultured with RPE cells.
Topics: Biomarkers; Cell Differentiation; Coculture Techniques; Electroretinography; Eye Proteins; Human Embryonic Stem Cells; Humans; Nystagmus, Optokinetic; Photoreceptor Cells; Real-Time Polymerase Chain Reaction; Retinal Pigment Epithelium; Stem Cells
PubMed: 34012231
DOI: No ID Found -
Progress in Retinal and Eye Research Jul 2019Photoreceptors are polarized neurons, with very specific subcellular compartmentalization and unique requirements for protein expression and trafficking. Each... (Review)
Review
Photoreceptors are polarized neurons, with very specific subcellular compartmentalization and unique requirements for protein expression and trafficking. Each photoreceptor contains an outer segment, the site of photon capture that initiates vision, an inner segment that houses the biosynthetic machinery and a synaptic terminal for signal transmission to downstream neurons. Outer segments and inner segments are connected by a connecting cilium (CC), the equivalent of a transition zone (TZ) of primary cilia. The connecting cilium is part of the basal body/axoneme backbone that stabilizes the outer segment. This report will update the reader on late developments in photoreceptor ciliogenesis and transition zone formation, specifically in mouse photoreceptors, focusing on early events in photoreceptor ciliogenesis. The connecting cilium, an elongated and narrow structure through which all outer segment proteins and membrane components must traffic, functions as a gate that controls access to the outer segment. Here we will review genes and their protein products essential for basal body maturation and for CC/TZ genesis, sorted by phenotype. Emphasis is given to naturally occurring mouse mutants and gene knockouts that interfere with CC/TZ formation and ciliogenesis.
Topics: Animals; Basal Bodies; Cilia; Membrane Proteins; Models, Animal; Photoreceptor Cells; Protein Transport; Signal Transduction
PubMed: 30590118
DOI: 10.1016/j.preteyeres.2018.12.004 -
Annual Review of Vision Science Sep 2020Photoreceptors are highly specialized sensory neurons with unique metabolic and physiological requirements. These requirements are partially met by Müller glia and... (Review)
Review
Photoreceptors are highly specialized sensory neurons with unique metabolic and physiological requirements. These requirements are partially met by Müller glia and cells of the retinal pigment epithelium (RPE), which provide essential metabolites, phagocytose waste, and control the composition of the surrounding microenvironment. A third vital supporting cell type, the retinal microglia, can provide photoreceptors with neurotrophic support or exacerbate neuroinflammation and hasten neuronal cell death. Understanding the physiological requirements for photoreceptor homeostasis and the factors that drive microglia to best promote photoreceptor survival has important implications for the treatment and prevention of blinding degenerative diseases like retinitis pigmentosa and age-related macular degeneration.
Topics: Animals; Apoptosis; Ependymoglial Cells; Humans; Macrophage Activation; Phagocytosis; Photoreceptor Cells; Retinal Cone Photoreceptor Cells; Retinal Degeneration; Retinal Pigment Epithelium; Signal Transduction
PubMed: 32936734
DOI: 10.1146/annurev-vision-121219-081730