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The Journal of Biological Chemistry Feb 2022The breakdown of all-trans-retinal (atRAL) clearance is closely associated with photoreceptor cell death in dry age-related macular degeneration (AMD) and autosomal...
The breakdown of all-trans-retinal (atRAL) clearance is closely associated with photoreceptor cell death in dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1), but its mechanisms remain elusive. Here, we demonstrate that activation of gasdermin E (GSDME) but not gasdermin D promotes atRAL-induced photoreceptor damage by activating pyroptosis and aggravating apoptosis through a mitochondria-mediated caspase-3-dependent signaling pathway. Activation of c-Jun N-terminal kinase was identified as one of the major causes of mitochondrial membrane rupture in atRAL-loaded photoreceptor cells, resulting in the release of cytochrome c from mitochondria to the cytosol, where it stimulated caspase-3 activation required for cleavage of GSDME. Aggregation of the N-terminal fragment of GSDME in the mitochondria revealed that GSDME was likely to penetrate mitochondrial membranes in photoreceptor cells after atRAL exposure. ABC (subfamily A, member 4) and all-trans-retinol dehydrogenase 8 are two key proteins responsible for clearing atRAL in the retina. Abca4Rdh8 mice exhibit serious defects in atRAL clearance upon light exposure and serve as an acute model for dry AMD and STGD1. We found that N-terminal fragment of GSDME was distinctly localized in the photoreceptor outer nuclear layer of light-exposed Abca4Rdh8 mice. Of note, degeneration and caspase-3 activation in photoreceptors were significantly alleviated in Abca4Rdh8Gsdme mice after exposure to light. The results of this study indicate that GSDME is a common causative factor of photoreceptor pyroptosis and apoptosis arising from atRAL overload, suggesting that repressing GSDME may represent a potential treatment of photoreceptor atrophy in dry AMD and STGD1.
Topics: ATP-Binding Cassette Transporters; Animals; Caspase 3; Mice; Photoreceptor Cells; Pore Forming Cytotoxic Proteins; Retina; Retinaldehyde; Stargardt Disease
PubMed: 34973334
DOI: 10.1016/j.jbc.2021.101553 -
Progress in Retinal and Eye Research Jul 2022The retinal pigment epithelium-photoreceptor interphase is renewed each day in a stunning display of cellular interdependence. While photoreceptors use photosensitive... (Review)
Review
The retinal pigment epithelium-photoreceptor interphase is renewed each day in a stunning display of cellular interdependence. While photoreceptors use photosensitive pigments to convert light into electrical signals, the RPE supports photoreceptors in their function by phagocytizing shed photoreceptor tips, regulating the blood retina barrier, and modulating inflammatory responses, as well as regenerating the 11-cis-retinal chromophore via the classical visual cycle. These processes involve multiple protein complexes, tightly regulated ligand-receptors interactions, and a plethora of lipids and protein-lipids interactions. The role of lipids in maintaining a healthy interplay between the RPE and photoreceptors has not been fully delineated. In recent years, novel technologies have resulted in major advancements in understanding several facets of this interplay, including the involvement of lipids in phagocytosis and phagolysosome function, nutrient recycling, and the metabolic dependence between the two cell types. In this review, we aim to integrate the complex role of lipids in photoreceptor and RPE function, emphasizing the dynamic exchange between the cells as well as discuss how these processes are affected in aging and retinal diseases.
Topics: Blood-Retinal Barrier; Humans; Lipids; Photoreceptor Cells; Retinal Diseases; Retinal Pigment Epithelium
PubMed: 34971765
DOI: 10.1016/j.preteyeres.2021.101037 -
Seminars in Cell & Developmental Biology Oct 2020The lamprey is an important non-model vertebrate because it is an agnathan or jawless vertebrate and belongs to the superclass cyclostomata, a group that split off from... (Review)
Review
The lamprey is an important non-model vertebrate because it is an agnathan or jawless vertebrate and belongs to the superclass cyclostomata, a group that split off from the rest of the vertebrates 500 million years ago. Investigation of the lamprey retina may therefore reveal attributes of visual function that were characteristic of even the most primitive vertebrates. The rod and cone photoreceptors are a striking example, because the biochemistry and physiology of phototransduction is remarkably similar between lamprey and the rest of the vertebrates, including mammals. The fundamental mechanism of light sensation seems therefore to have emerged very early in the evolution of vertebrates in the late Cambrian. Some other characteristics of the retina are also similar and may be very old, but other features such as the morphology of ganglion cells are rather different in lamprey and other vertebrates. Even these differences may provide new insight into the various mechanisms vertebrates use for visual detection.
Topics: Animals; Lampreys; Retina; Retinal Cone Photoreceptor Cells
PubMed: 31711759
DOI: 10.1016/j.semcdb.2019.10.008 -
The Journal of Experimental Biology Jul 2021Time is largely a hidden variable in vision. It is the condition for seeing interesting things such as spatial forms and patterns, colours and movements in the external...
Time is largely a hidden variable in vision. It is the condition for seeing interesting things such as spatial forms and patterns, colours and movements in the external world, and yet is not meant to be noticed in itself. Temporal aspects of visual processing have received comparatively little attention in research. Temporal properties have been made explicit mainly in measurements of resolution and integration in simple tasks such as detection of spatially homogeneous flicker or light pulses of varying duration. Only through a mechanistic understanding of their basis in retinal photoreceptors and circuits can such measures guide modelling of natural vision in different species and illuminate functional and evolutionary trade-offs. Temporal vision research would benefit from bridging traditions that speak different languages. Towards that goal, I here review studies from the fields of human psychophysics, retinal physiology and neuroethology, with a focus on fundamental constraints set by early vision.
Topics: Humans; Photoreceptor Cells, Vertebrate; Retina; Vision, Ocular; Visual Perception
PubMed: 34328511
DOI: 10.1242/jeb.222679 -
Eye (London, England) Nov 2021In human retina, photoreceptor cell death (PCD) is a slow but conspicuous event, which continues with aging. Rods die earlier than cones, the latter continue to alter in... (Review)
Review
In human retina, photoreceptor cell death (PCD) is a slow but conspicuous event, which continues with aging. Rods die earlier than cones, the latter continue to alter in a subtle manner until advanced aging. This review summarizes the existing information on age-related changes in photoreceptor cells, especially cones and analyses the possible associated factors. Oxidative and nitrosative stress are involved in photoreceptor alterations, which may stem from light and iron toxicity and other sources. Lipid peroxidation in macular photoreceptor outer segments and mitochondrial aberrations are prominent in aging. It is important to understand how those changes ultimately trigger PCD. The redistribution of calbindin D-28K and long/middle-wavelength-sensitive opsin in the parafoveal and perifoveal cones, anomalies in their somata and axons are strong predictors of their increasing vulnerability with aging. Signs of reduced autophagy, with autophagosomes containing organelle remnants are seen in aging photoreceptor cells. Currently, mechanisms that lead to human PCD are unknown; some observations favour apoptosis as a pathway. Since cones appear to change slowly, there is an opportunity to reverse those changes before they die. Therefore, a full understanding of how cones alter and the molecular pathways they utilize for survival must be the future research goal. Recent approaches to prevent PCD in aging and diseases are highlighted.
Topics: Aging; Humans; Immunohistochemistry; Retina; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells
PubMed: 34079093
DOI: 10.1038/s41433-021-01602-1 -
Proceedings of the National Academy of... May 2022Myopia is the commonest visual impairment. Several genetic loci confer risk, but mechanisms by which they do this are unknown. Retinal signals drive eye growth, and...
Myopia is the commonest visual impairment. Several genetic loci confer risk, but mechanisms by which they do this are unknown. Retinal signals drive eye growth, and myopia usually results from an excessively long eye. The common variant most strongly associated with myopia is near the GJD2 gene, encoding connexin-36, which forms retinal gap junctions. Light-evoked responses of retinal neurons can be recorded noninvasively as the electroretinogram (ERG). We analyzed these responses from 186 adult twin volunteers who had been genotyped at this locus. Participants underwent detailed ERG recordings incorporating international standard stimuli as well as experimental protocols aiming to separate dark-adapted rod- and cone-driven responses. A mixed linear model was used to explore association between allelic dosage at the locus and international standard ERG parameters after adjustment for age, sex, and family structure. Significant associations were found for parameters of light-adapted, but not dark-adapted, responses. Further investigation of isolated rod- and cone-driven ERGs confirmed associations with cone-driven, but not rod-driven, a-wave amplitudes. Comparison with responses to similar experimental stimuli from a patient with a prior central retinal artery occlusion, and from two patients with selective loss of ON-bipolar cell signals, was consistent with the associated parameters being derived from signals from cone-driven OFF-bipolar cells. Analysis of single-cell transcriptome data revealed strongest GJD2 expression in cone photoreceptors; bipolar cell expression appeared strongest in OFF-bipolar cells and weakest in rod-driven ON-bipolar cells. Our findings support a potential role for altered signaling in cone-driven OFF pathways in myopia development.
Topics: Electroretinography; Genome-Wide Association Study; Humans; Myopia; Polymorphism, Genetic; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells
PubMed: 35594404
DOI: 10.1073/pnas.2119675119 -
Ophthalmic Genetics Jun 2022Rods and cones are photoreceptor neurons in the retina that are required for visual sensation in vertebrates, wherein the perception of vision is initiated when these...
BACKGROUND
Rods and cones are photoreceptor neurons in the retina that are required for visual sensation in vertebrates, wherein the perception of vision is initiated when these neurons respond to photons in the light stimuli. The photoreceptor cell is structurally studied as outer segments (OS) and inner segments (IS) where proper protein sorting, localization, and compartmentalization are critical for phototransduction, visual function, and survival. In human retinal diseases, improper protein transport to the OS or mislocalization of proteins to the IS and other cellular compartments could lead to impaired visual responses and photoreceptor cell degeneration that ultimately cause loss of visual function.
RESULTS
Therefore, studying and identifying mechanisms involved in facilitating and maintaining proper protein transport in photoreceptor cells would help our understanding of pathologies involving retinal cell degeneration in inherited retinal dystrophies, age-related macular degeneration, and Usher Syndrome.
CONCLUSIONS
Our mini-review will discuss mechanisms of protein transport within photoreceptors and introduce a novel role for an unconventional motor protein, MYO1C, in actin-based motor transport of the visual chromophore Rhodopsin to the OS, in support of phototransduction and visual function.
Topics: Animals; Humans; Protein Transport; Retina; Retinal Cone Photoreceptor Cells; Retinal Degeneration; Retinal Rod Photoreceptor Cells; Vision, Ocular
PubMed: 35470760
DOI: 10.1080/13816810.2022.2062391 -
International Journal of Molecular... Nov 2022Diabetic retinopathy (DR) was identified as a leading cause of blindness and vision impairment in 2020. In addition to vasculopathy, DR has been found to involve retinal...
Diabetic retinopathy (DR) was identified as a leading cause of blindness and vision impairment in 2020. In addition to vasculopathy, DR has been found to involve retinal neurons, including amacrine cells and retinal ganglion cells. Despite possessing features that are susceptible to diabetic conditions, photoreceptor cells have received relatively little attention with respect to the development of DR. Until recently, studies have suggested that photoreceptors secret proinflammatory molecules and produce reactive oxygen species that contribute to the development of DR. However, the effect of hyperglycemia on photoreceptors and its underlying mechanism remains elusive. In this study, the direct effect of high glucose on photoreceptor cells was investigated using a 661w photoreceptor-like cell line. A data-independent sequential window acquisition of all theoretical mass spectra (SWATH)-based proteomic approach was employed to study changes induced by high glucose in the proteomic profile of the cells. The results indicated that high glucose induced a significant increase in apoptosis and ROS levels in the 661w cells, with mitochondrial dysfunction among the major affected canonical pathways. The involvement of mitochondrial dysfunction was further supported by increased mitochondrial fission and reduced mitochondrial bioenergetics. Collectively, these findings provide a biological basis for a possible role of photoreceptors in the pathogenesis of DR.
Topics: Humans; Proteomics; Hyperglycemia; Photoreceptor Cells; Diabetic Retinopathy; Mitochondria; Glucose
PubMed: 36362154
DOI: 10.3390/ijms232113366 -
Bulletin of Experimental Biology and... Aug 2022Immunohistochemical and ultrastructural analysis revealed signs of structural alterations in neurons and autophagy in all layers of the human retina at the end-stage...
Immunohistochemical and ultrastructural analysis revealed signs of structural alterations in neurons and autophagy in all layers of the human retina at the end-stage glaucoma. The most pronounced destructive changes associated with swelling and destruction of mitochondria, endoplasmic reticulum, and Golgi apparatus, as well as structural signs of impaired synaptic activity and apoptosis were noted in ganglion, bipolar, and amacrine neurons. In the structure of photoreceptor cells, alone with destructive processes associated with structural alterations of rods and cones in the outer membrane discs, as well as swelling of organelles, we observed processes aimed at the maintenance of cell homeostasis. Structural signs of autophagy (mainly mitophagy) and changes of the ultrastructural organization in rod neurons were more pronounced than in cones.
Topics: Autophagy; Glaucoma; Humans; Photoreceptor Cells; Retina; Retinal Neurons; Synapses
PubMed: 36058974
DOI: 10.1007/s10517-022-05563-7 -
Advanced Biology May 2021In nature, photoreceptor proteins undergo molecular responses to light, that exhibit supreme fidelity in time and space and generally occur under mild reaction...
In nature, photoreceptor proteins undergo molecular responses to light, that exhibit supreme fidelity in time and space and generally occur under mild reaction conditions. To unlock these traits for material science, the light-induced homodimerization of light-oxygen-voltage (LOV) photoreceptors is leveraged to control the assembly of gold nanoparticles. Conjugated to genetically encodable LOV proteins, the nanoparticles are monodispersed in darkness but rapidly assemble into large aggregates upon blue-light exposure. The study establishes a new modality for reaction control in macromolecular chemistry and thus augurs enhanced precision in space and time in diverse applications of gold nanoparticles.
Topics: Gold; Metal Nanoparticles; Oxygen; Photoreceptor Cells
PubMed: 34028211
DOI: 10.1002/adbi.202000179