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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 -
IEEE Transactions on Ultrasonics,... Dec 2022Ultrasound neuromodulation is an emerging technology. A significant amount of effort has been devoted to investigating the feasibility of noninvasive ultrasound retinal... (Review)
Review
Ultrasound neuromodulation is an emerging technology. A significant amount of effort has been devoted to investigating the feasibility of noninvasive ultrasound retinal stimulation. Recent studies have shown that ultrasound can activate neurons in healthy and degenerated retinas. Specifically, high-frequency ultrasound can evoke localized neuron responses and generate patterns in visual circuits. In this review, we recapitulate pilot studies on ultrasound retinal stimulation, compare it with other neuromodulation technologies, and discuss its advantages and limitations. An overview of the opportunities and challenges to develop a noninvasive retinal prosthesis using high-frequency ultrasound is also provided.
Topics: Retina; Visual Prosthesis; Ultrasonography
PubMed: 36343006
DOI: 10.1109/TUFFC.2022.3220568 -
American Journal of Ophthalmology Aug 2021To determine classification criteria for birdshot chorioretinitis.
PURPOSE
To determine classification criteria for birdshot chorioretinitis.
DESIGN
Machine learning of cases with birdshot chorioretinitis and 8 other posterior uveitides.
METHODS
Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior uveitides / panuveitides. The resulting criteria were evaluated on the validation set.
RESULTS
One thousand sixty-eight cases of posterior uveitides, including 207 cases of birdshot chorioretinitis, were evaluated by machine learning. Key criteria for birdshot chorioretinitis included a multifocal choroiditis with (1) the characteristic appearance of a bilateral multifocal choroiditis with cream-colored or yellow-orange, oval or round choroidal spots ("birdshot" spots); (2) absent to mild anterior chamber inflammation; and (3) absent to moderate vitreous inflammation; or multifocal choroiditis with positive HLA-A29 testing and either classic "birdshot spots" or characteristic imaging on indocyanine green angiography. Overall accuracy for posterior uveitides was 93.9% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for birdshot chorioretinitis were 10% in the training set and 0% in the validation set.
CONCLUSIONS
The criteria for birdshot chorioretinitis had a low misclassification rate and seemed to perform sufficiently well for use in clinical and translational research.
Topics: Birdshot Chorioretinopathy; Choroid; Consensus; Female; Fluorescein Angiography; Fundus Oculi; Humans; Machine Learning; Male; Middle Aged; Retina
PubMed: 33845003
DOI: 10.1016/j.ajo.2021.03.059 -
Experimental Eye Research May 2021Noninvasive in vivo imaging of the mouse retina is essential for eye research. However, imaging the mouse fundus is challenging due to its small size and requires... (Review)
Review
Noninvasive in vivo imaging of the mouse retina is essential for eye research. However, imaging the mouse fundus is challenging due to its small size and requires specialized equipment, maintenance, and training. These issues hinder the routine evaluation of the mouse retina. In this study, we developed a noncontact imaging system consisting of a smartphone, a 90D condensing lens, a homemade light diaphragm, a tripod, and a Bluetooth remote. With minimal training, examiners were able to capture fundus images from the mouse retina. We also found that fundus images captured using our system from wild type mice, mice with laser-induced retinal injury, and a mouse model of retinitis pigmentosa showed a quality similar to those captured using a commercial fundus camera. These images enabled us to identify normal structures and pathological changes in the mouse retina. Additionally, fluorescein angiography was possible with the smartphone system. We believe that the smartphone imaging system is low cost, simple, accessible, easy to operate, and suitable for the routine screening and examination of the mouse eye.
Topics: Animals; Fluorescein Angiography; Fundus Oculi; Mice; Ophthalmoscopy; Retina; Retinal Diseases; Smartphone
PubMed: 33675778
DOI: 10.1016/j.exer.2021.108530 -
Current Biology : CB Apr 2023Most defects causing retinal degeneration in retinitis pigmentosa (RP) are rod-specific mutations, but the subsequent degeneration of cones, which produces loss of...
Most defects causing retinal degeneration in retinitis pigmentosa (RP) are rod-specific mutations, but the subsequent degeneration of cones, which produces loss of daylight vision and high-acuity perception, is the most debilitating feature of the disease. To understand better why cones degenerate and how cone vision might be restored, we have made the first single-cell recordings of light responses from degenerating cones and retinal interneurons after most rods have died and cones have lost their outer-segment disk membranes and synaptic pedicles. We show that degenerating cones have functional cyclic-nucleotide-gated channels and can continue to give light responses, apparently produced by opsin localized either to small areas of organized membrane near the ciliary axoneme or distributed throughout the inner segment. Light responses of second-order horizontal and bipolar cells are less sensitive but otherwise resemble those of normal retina. Furthermore, retinal output as reflected in responses of ganglion cells is less sensitive but maintains spatiotemporal receptive fields at cone-mediated light levels. Together, these findings show that cones and their retinal pathways can remain functional even as degeneration is progressing, an encouraging result for future research aimed at enhancing the light sensitivity of residual cones to restore vision in patients with genetically inherited retinal degeneration.
Topics: Humans; Retinal Degeneration; Retinal Cone Photoreceptor Cells; Retina; Retinitis Pigmentosa; Color Vision
PubMed: 36977418
DOI: 10.1016/j.cub.2023.03.007 -
Biomedicine & Pharmacotherapy =... May 2022This review focuses on retina degeneration occurring during glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP),... (Review)
Review
This review focuses on retina degeneration occurring during glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP), and on the potential therapeutic use of triads of repositioned medicines, addressed to distinct but complementary targets, to prevent, delay or stop retina cell death. Although myriad pathogenic mechanisms have been implicated in these disorders, common signaling pathways leading to apoptotic cell death to all of them, and to all neurodegenerative diseases are (i) calcium dyshomeostasis/excitotoxicity; (ii) oxidative stress/mitochondrial dysfunction, and (iii) neuroinflammation/P2X7 receptor activation. From a therapeutic point of view, it is relevant to consider the multitarget approach based on the use of combined medicines acting on complementary pathogenic mechanisms that has been highly successful in the treatment of chronic diseases such as cancer, AIDS, pain, hypertension, Parkinson's disease, cardiac failure, depression, or the epilepsies as the basic mechanisms of cell death do not differ between the different CNS degenerative diseases. We suggest the multi-target therapy approach could be more effective compared with single-drug treatments. Used at doses lower than standard, these triads may also be safer and more efficient. After the establishment of a proof-of-concept in animal models of retinal degeneration, potential successful preclinical trials of such combinations may eventually drive to test this concept in clinical trials in patients, first to evaluate the safety and efficacy of the drug combinations in humans and then their therapeutic advantages, if any, seeking the prevention and/or the delay of retina degeneration and blindness.
Topics: Animals; Diabetic Retinopathy; Humans; Neurodegenerative Diseases; Neuroprotection; Retina; Retinal Degeneration
PubMed: 36068774
DOI: 10.1016/j.biopha.2022.112911 -
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 -
Graefe's Archive For Clinical and... Oct 2022In many retinal pathological conditions, rod and cone degeneration differs. For example, the early-onset maculopathy Stargardts disease type 1 (STGD1) is typified by... (Review)
Review
PURPOSE
In many retinal pathological conditions, rod and cone degeneration differs. For example, the early-onset maculopathy Stargardts disease type 1 (STGD1) is typified by loss of cones while rods are often less affected. We wanted to examine whether there exist intrinsic membrane differences between rods and cones that might explain such features.
METHODS
Abca4 mRNA and protein levels were quantified in rod- and cone-enriched samples from wild-type and Nrl mice retinas; rod- and cone-enriched outer segments (ROS and COS respectively) were prepared from pig retinas, and total lipids were analyzed by flame ionization, chromatography, and tandem mass spectrometry. Immunohistochemical staining of cone-rich rodent Arvicanthis ansorgei retinas was conducted, and ultra-high performance liquid chromatography of lipid species in porcine ROS and COS was performed.
RESULTS
Abca4 mRNA and Abca4 protein content was significantly higher (50-300%) in cone compared to rod-enriched samples. ROS and COS displayed dramatic differences in several lipids, including very long chain poly-unsaturated fatty acids (VLC-PUFAs), especially docosahexaenoic acid (DHA, 22:6n-3): ROS 20.6% DHA, COS 3.3% (p < 0.001). VLC-PUFAs (> 50 total carbons) were virtually absent from COS. COS were impoverished (> 6× less) in phosphatidylethanolamine compared to ROS. ELOVL4 ("ELOngation of Very Long chain fatty acids 4") antibody labelled Arvicanthis cones only very weakly compared to rods. Finally, there were large amounts (905 a.u.) of the bisretinoid A2PE in ROS, whereas it was much lower (121 a.u., ~ 7.5-fold less) in COS fractions. In contrast, COS contained fivefold higher amounts of all-trans-retinal dimer (115 a.u. compared to 22 a.u. in rods).
CONCLUSIONS
Compared to rods, cones expressed higher levels of Abca4 mRNA and Abca4 protein, were highly impoverished in PUFA (especially DHA) and phosphatidylethanolamine, and contained significant amounts of all-trans-retinal dimer. Based on these and other data, we propose that in contrast to rods, cones are preferentially vulnerable to stress and may die through direct cellular toxicity in pathologies such as STGD1.
Topics: Animals; Docosahexaenoic Acids; Murinae; Phosphatidylethanolamines; RNA, Messenger; Reactive Oxygen Species; Retinal Cone Photoreceptor Cells; Retinal Degeneration; Retinaldehyde; Swine
PubMed: 35524799
DOI: 10.1007/s00417-022-05684-9 -
BMC Ophthalmology Jan 2023To compare the retinal thicknesses (RT) and choroidal thicknesses (CT) in retinitis pigmentosa (RP) children with those of healthy children using enhanced depth imaging...
PURPOSE
To compare the retinal thicknesses (RT) and choroidal thicknesses (CT) in retinitis pigmentosa (RP) children with those of healthy children using enhanced depth imaging (EDI) optical coherence tomography (OCT). The RT and CT in different genetic subgroups of autosomal dominant RP (ADRP) and X-linked inheritance RP (XLRP) were further studied to investigate the characteristics of retinal and choroidal changes in the early stages of RP.
METHOD
A retrospective analysis was performed on a group of patients with RP who underwent EDI-OCT. Thirty-two children (64 eyes) with RP and 28 age- and refraction-matched healthy children (56 eyes) were included in the study. Seven of the 32 RP children (14 eyes) had X-linked inheritance RP, and 10 (20 eyes) had autosomal dominant inheritance RP. RT and CT were measured by optical coherence tomography and compared between the 32 children with RP and 28 controls and between 7 XLRP and 10 ADRP children.
RESULT
Among the 32 children with RP, there were 18 males and 14 females with an average age of 6.6 ± 2.4 years. The mean RT was smaller in the RP group than in the control group at all of the locations. The mean temporal CT was smaller in the RP group (243.76 ± 60.82 μm) than in the control group (275.23 ± 40.92 μm) (P = 0.001), while there was no significant thinning on the foveal or nasal side. The best-corrected visual acuity of the XLRP group (0.40 ± 0.19) was worse than that of the ADRP group (0.68 ± 0.21) (P = 0.001), but the disease duration was the same (P = 0.685). The mean foveal RT was smaller in the XLRP group (173.85 ± 22.87 μm) than in the ADRP group (192.20 ± 9.70 μm) (P = 0.003), while there was no significant thinning at the other locations we studied. The mean temporal CT was smaller in the XLRP group (211.21 ± 69.41 μm) than in the ADRP group (274.45 ± 57.91 μm) (P = 0.007); CT measurements in XLRP children showed a more severe reduction on the temporal side.
CONCLUSION
The choroid in RP children was preferentially smaller on the temporal side of the macula, and retinal thinning was relatively extensive. Children with RP have strong clinical and genetic heterogeneity. The XLRP children demonstrated greater RT reduction at the fovea and greater CT reduction at the temporal side of the macula than the ADRP children. Our findings also provide evidence that the changes in thicknesses may be indicative of the greater severity of XLRP versus ADRP in the early stage.
Topics: Male; Female; Humans; Child; Child, Preschool; Retrospective Studies; Retina; Retinitis Pigmentosa; Retinal Degeneration; Choroid; Tomography, Optical Coherence
PubMed: 36650468
DOI: 10.1186/s12886-023-02772-0 -
Stem Cell Research & Therapy Nov 2023Inherited retinal diseases (IRDs) can induce severe sight-threatening retinal degeneration and impose a considerable economic burden on patients and society, making... (Review)
Review
Inherited retinal diseases (IRDs) can induce severe sight-threatening retinal degeneration and impose a considerable economic burden on patients and society, making efforts to cure blindness imperative. Transgenic animals mimicking human genetic diseases have long been used as a primary research tool to decipher the underlying pathogenesis, but there are still some obvious limitations. As an alternative strategy, patient-derived induced pluripotent stem cells (iPSCs), particularly three-dimensional (3D) organoid technology, are considered a promising platform for modeling different forms of IRDs, including retinitis pigmentosa, Leber congenital amaurosis, X-linked recessive retinoschisis, Batten disease, achromatopsia, and best vitelliform macular dystrophy. Here, this paper focuses on the status of patient-derived iPSCs and organoids in IRDs in recent years concerning disease modeling and therapeutic exploration, along with potential challenges for translating laboratory research to clinical application. Finally, the importance of human iPSCs and organoids in combination with emerging technologies such as multi-omics integration analysis, 3D bioprinting, or microfluidic chip platform are highlighted. Patient-derived retinal organoids may be a preferred choice for more accurately uncovering the mechanisms of human retinal diseases and will contribute to clinical practice.
Topics: Animals; Humans; Induced Pluripotent Stem Cells; Retina; Retinal Degeneration; Retinitis Pigmentosa; Organoids
PubMed: 38012786
DOI: 10.1186/s13287-023-03564-5