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Visual Neuroscience Sep 2020Vision loss, among the most feared complications of diabetes, is primarily caused by diabetic retinopathy, a disease that manifests in well-recognized, characteristic... (Review)
Review
Vision loss, among the most feared complications of diabetes, is primarily caused by diabetic retinopathy, a disease that manifests in well-recognized, characteristic microvascular lesions. The reasons for retinal susceptibility to damage in diabetes are unclear, especially considering that microvascular networks are found in all tissues. However, the unique metabolic demands of retinal neurons could account for their vulnerability in diabetes. Photoreceptors are the first neurons in the visual circuit and are also the most energy-demanding cells of the retina. Here, we review experimental and clinical evidence linking photoreceptors to the development of diabetic retinopathy. We then describe the influence of retinal illumination on photoreceptor metabolism, effects of light modulation on the severity of diabetic retinopathy, and recent clinical trials testing the treatment of diabetic retinopathy with interventions that impact photoreceptor metabolism. Finally, we introduce several possible mechanisms that could link photoreceptor responses to light and the development of retinal vascular disease in diabetes. Collectively, these concepts form the basis for a growing body of investigative efforts aimed at developing novel pharmacologic and nonpharmacologic tools that target photoreceptor physiology to treat a very common cause of blindness across the world.
Topics: Diabetes Mellitus; Diabetic Retinopathy; Humans; Photoreceptor Cells; Retina
PubMed: 32921331
DOI: 10.1017/S0952523820000061 -
Biomolecules Jul 2022Photoreceptors are sensitive neuronal cells with great metabolic demands, as they are responsible for carrying out visual phototransduction, a complex and multistep... (Review)
Review
Photoreceptors are sensitive neuronal cells with great metabolic demands, as they are responsible for carrying out visual phototransduction, a complex and multistep process that requires the exquisite coordination of a large number of signalling protein components. Therefore, the viability of photoreceptors relies on mechanisms that ensure a well-balanced and functional proteome that maintains the protein homeostasis, or proteostasis, of the cell. This review explores how the different isoforms of Hsp90, including the cytosolic Hsp90α/β, the mitochondrial TRAP1, and the ER-specific GRP94, are involved in the different proteostatic mechanisms of photoreceptors, and elaborates on Hsp90 function when retinal homeostasis is disturbed. In addition, several studies have shown that chemical manipulation of Hsp90 has significant consequences, both in healthy and degenerating retinae, and this can be partially attributed to the fact that Hsp90 interacts with important photoreceptor-associated client proteins. Here, the interaction of Hsp90 with the retina-specific client proteins PDE6 and GRK1 will be further discussed, providing additional insights for the role of Hsp90 in retinal disease.
Topics: HSP90 Heat-Shock Proteins; Humans; Photoreceptor Cells; Proteostasis; Retina
PubMed: 35883534
DOI: 10.3390/biom12070978 -
Translational Vision Science &... Nov 2022The cone-dominant, 13-lined ground squirrel (13-LGS) retina mimics the human central retina, but a thorough examination of retinal development in this species has not...
PURPOSE
The cone-dominant, 13-lined ground squirrel (13-LGS) retina mimics the human central retina, but a thorough examination of retinal development in this species has not been reported. Here, the embryonic and postnatal development of the 13-LGS retina was studied to further characterize 13-LGS as a practical alternative animal model for investigating cone-based vision in health and disease.
METHODS
The spatiotemporal expression of key progenitor and cell type markers was examined in retinas from defined embryonic and postnatal stages using immunohistochemistry. Postnatal gene expression changes were validated by quantitative PCR.
RESULTS
The 13-LGS neuroblastic layer expressed key progenitor markers (Sox2, Vsx2, Pax6, and Lhx2) at E18. Sequential cell fate determination evidenced by the first appearance of cell-type-specific marker labeling was at embryonic stage 18 (E18) with ganglion cells (Brn-3A, HuC/D) and microglia (Iba1); at E22.5 with photoreceptor progenitors (Otx2, recoverin) followed shortly by horizontal and amacrine cells (Lhx1, Oc1) at E24 to E25.5; and at postnatal stage 15 (P15) with bipolar cells (Vsx1, CaBP5) and Müller glia cells (GS, Rlbp1). Photoreceptor maturation indicated by opsin-positive outer segments and peanut agglutinin (PNA) labeling of cone sheaths was completed at the time of eye opening (P21-P24).
CONCLUSIONS
The timeline and order of retinal cell development in the 13-LGS generally matches that recorded from other mammalian models but with a stark variation in the proportion of various cell types due to cone-dense photoreceptors.
TRANSLATIONAL RELEVANCE
This thorough examination of an emerging translationally relevant cone-dominant specie provides a baseline for future disease modeling and stem cell approach studies of human vision.
Topics: Animals; Humans; Retinal Cone Photoreceptor Cells; Sciuridae; Retina; Amacrine Cells; Ependymoglial Cells
PubMed: 36409292
DOI: 10.1167/tvst.11.11.17 -
Progress in Retinal and Eye Research Jan 2023Retinal gene supplementation therapy such as the first approved one, voretigene neparvovec, delivers a functioning copy of the missing gene enabling the protein... (Review)
Review
Retinal gene supplementation therapy such as the first approved one, voretigene neparvovec, delivers a functioning copy of the missing gene enabling the protein transcription in retinal cells and restore visual functions. After gene supplementation for the genetic defect, a complex network of functional regeneration is the consequence, whereas the extent is very individualized. Diagnostic and functional testings that have been used routinely by ophthalmologists so far to define the correct diagnosis, cannot be applied in the new context of defining small, sometimes subtle changes in visual functions. New view on retinal diagnostics is needed to understand this processes that define safety and efficacy of the treatment. Not only does vision have many aspects that must be addressed by specific evaluations and imaging techniques, but objective readouts of local retinal function for rods and cones separately have been an unmet need until recently. A reliable test-retest variability is necessary in rare diseases such as inherited retinal dystrophies, because statistics are often not applicable due to a low number of participants. Methods for a reliable individual evaluation of the therapy success are needed. In this manuscript we present an elaboration on retinal diagnostics combining psychophysics (eg. full-field stimulus threshold or dark adapted perimetry) as well as objective measures for local retinal function (eg. photopic and scotopic chromatic pupil campimetry) and retinal imaging for a meaningful workflow to apply in evaluation of the individual success in patients receiving gene therapy for photoreceptor diseases.
Topics: Humans; Vision, Ocular; Retinal Rod Photoreceptor Cells; Retinal Dystrophies; Visual Field Tests; Retinal Cone Photoreceptor Cells
PubMed: 36096933
DOI: 10.1016/j.preteyeres.2022.101115 -
Pflugers Archiv : European Journal of... Sep 2021Light-evoked voltage responses of rod and cone photoreceptor cells in the vertebrate retina must be converted to a train of synaptic vesicle release events for... (Review)
Review
Light-evoked voltage responses of rod and cone photoreceptor cells in the vertebrate retina must be converted to a train of synaptic vesicle release events for transmission to downstream neurons. This review discusses the processes, proteins, and structures that shape this critical early step in vision, focusing on studies from salamander retina with comparisons to other experimental animals. Many mechanisms are conserved across species. In cones, glutamate release is confined to ribbon release sites although rods are also capable of release at non-ribbon sites. The role of non-ribbon release in rods remains unclear. Release from synaptic ribbons in rods and cones involves at least three vesicle pools: a readily releasable pool (RRP) matching the number of membrane-associated vesicles along the ribbon base, a ribbon reserve pool matching the number of additional vesicles on the ribbon, and an enormous cytoplasmic reserve. Vesicle release increases in parallel with Ca channel activity. While the opening of only a few Ca channels beneath each ribbon can trigger fusion of a single vesicle, sustained release rates in darkness are governed by the rate at which the RRP can be replenished. The number of vacant release sites, their functional status, and the rate of vesicle delivery in turn govern replenishment. Along with an overview of the mechanisms of exocytosis and endocytosis, we consider specific properties of ribbon-associated proteins and pose a number of remaining questions about this first synapse in the visual system.
Topics: Animals; Calcium Channels; Humans; Photic Stimulation; Retina; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Synapses; Synaptic Transmission
PubMed: 33779813
DOI: 10.1007/s00424-021-02548-9 -
Progress in Retinal and Eye Research Jan 2021The photochemistry of vision employs opsins and geometric isomerization of their covalently bound retinylidine chromophores. In different animal classes, these light... (Review)
Review
The photochemistry of vision employs opsins and geometric isomerization of their covalently bound retinylidine chromophores. In different animal classes, these light receptors associate with distinct G proteins that either hyperpolarize or depolarize photoreceptor membranes. Vertebrates also use the acidic form of chromophore, retinoic acid, as the ligand of nuclear hormone receptors that orchestrate eye development. To establish and sustain these processes, animals must acquire carotenoids from the diet, transport them, and metabolize them to chromophore and retinoic acid. The understanding of carotenoid metabolism, however, lagged behind our knowledge about the biology of their receptor molecules. In the past decades, much progress has been made in identifying the genes encoding proteins that mediate the transport and enzymatic transformations of carotenoids and their retinoid metabolites. Comparative analysis in different animal classes revealed how evolutionary tinkering with a limited number of genes evolved different biochemical strategies to supply photoreceptors with chromophore. Mutations in these genes impair carotenoid metabolism and induce various ocular pathologies. This review summarizes this advancement and introduces the involved proteins, including the homeostatic regulation of their activities.
Topics: Animals; Biological Transport; Carotenoids; Carrier Proteins; Diet; Homeostasis; Humans; Photoreceptor Cells; Retinoids; Vision, Ocular
PubMed: 32339666
DOI: 10.1016/j.preteyeres.2020.100864 -
Journal of the American Association For... Jan 2023Light is an extrinsic factor that exerts widespread influence on the regulation of circadian, physiologic, hormonal, metabolic, and behavioral systems of all animals,... (Review)
Review
Light is an extrinsic factor that exerts widespread influence on the regulation of circadian, physiologic, hormonal, metabolic, and behavioral systems of all animals, including those used in research. These wide-ranging biologic effects of light are mediated by distinct photoreceptors, the melanopsin-containing intrinsically photosensitive retinal ganglion cells of the nonvisual system, which interact with the rods and cones of the conventional visual system. Here, we review the nature of light and circadian rhythms, current industry practices and standards, and our present understanding of the neurophysiology of the visual and nonvisual systems. We also consider the implications of this extrinsic factor for vivarium measurement, production, and technological application of light, and provide simple recommendations on artificial lighting for use by regulatory authorities, lighting manufacturers, designers, engineers, researchers, and research animal care staff that ensure best practices for optimizing animal health and wellbeing and, ultimately, improving scientific outcomes.
Topics: Animals; Lighting; Retinal Ganglion Cells; Photoreceptor Cells; Circadian Rhythm
PubMed: 36755210
DOI: 10.30802/AALAS-JAALAS-23-000003 -
The Journal of Thoracic and... Dec 2020
Topics: Ebstein Anomaly; Humans; Retinal Cone Photoreceptor Cells
PubMed: 32682585
DOI: 10.1016/j.jtcvs.2020.06.049 -
International Journal of Molecular... Nov 2022Retinal organoids (ROs) are three-dimensional retinal tissues, which are differentiated in vitro from induced pluripotent stem cells (iPSC), ultimately forming all main...
Retinal organoids (ROs) are three-dimensional retinal tissues, which are differentiated in vitro from induced pluripotent stem cells (iPSC), ultimately forming all main retinal cell types under defined culture conditions. ROs show several highly specialized retinal features, including the outgrowth of photoreceptor outer segments (OSs). In vivo, the photoreceptor OSs are enveloped and maintained by protrusions of retinal pigment epithelium (RPE) cells, the so-called apical microvilli, while ROs fail to recapitulate this critical interaction in culture development. Here, we define specific co-culture conditions aiming to compensate for the missing physical proximity of RPE and OSs in RO development. Accordingly, functional RPE cells and ROs were differentiated simultaneously from the same iPSC clone, the former resulting in byproduct RPE or bRPE cells. While some co-culture approaches indicated a temporary functional interaction between bRPE and RO photoreceptors, they did not improve the photoreceptor histoarchitecture. In contrast, embedding ROs in a basement membrane extract without bRPE cells showed a robust improvement in the rate of photoreceptor OS retention. RO embedding is a quick and easy method that greatly enhances the preservation of photoreceptor OSs, an important structure for modelling retinal diseases with the involvement of photoreceptors.
Topics: Retinal Pigment Epithelium; Organoids; Retina; Induced Pluripotent Stem Cells; Cell Differentiation; Photoreceptor Cells
PubMed: 36499228
DOI: 10.3390/ijms232314893 -
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