-
JCI Insight Nov 2023Retinitis pigmentosa (RP) is the most common inherited retinal disease (IRD) and is characterized by photoreceptor degeneration and progressive vision loss. We report 4...
Retinitis pigmentosa (RP) is the most common inherited retinal disease (IRD) and is characterized by photoreceptor degeneration and progressive vision loss. We report 4 patients presenting with RP from 3 unrelated families with variants in TBC1D32, which to date has never been associated with an IRD. To validate TBC1D32 as a putative RP causative gene, we combined Xenopus in vivo approaches and human induced pluripotent stem cell-derived (iPSC-derived) retinal models. Our data showed that TBC1D32 was expressed during retinal development and that it played an important role in retinal pigment epithelium (RPE) differentiation. Furthermore, we identified a role for TBC1D32 in ciliogenesis of the RPE. We demonstrated elongated ciliary defects that resulted in disrupted apical tight junctions, loss of functionality (delayed retinoid cycling and altered secretion balance), and the onset of an epithelial-mesenchymal transition-like phenotype. Last, our results suggested photoreceptor differentiation defects, including connecting cilium anomalies, that resulted in impaired trafficking to the outer segment in cones and rods in TBC1D32 iPSC-derived retinal organoids. Overall, our data highlight a critical role for TBC1D32 in the retina and demonstrate that TBC1D32 mutations lead to RP. We thus identify TBC1D32 as an IRD-causative gene.
Topics: Humans; Induced Pluripotent Stem Cells; Retina; Retinitis Pigmentosa; Retinal Degeneration; Retinal Pigment Epithelium; Adaptor Proteins, Signal Transducing
PubMed: 37768732
DOI: 10.1172/jci.insight.169426 -
International Journal of Molecular... Nov 2023Diabetic retinopathy (DR) is a leading cause of vision impairment in the working-age population worldwide. Various modes of photoreceptor cell death contribute to the...
Diabetic retinopathy (DR) is a leading cause of vision impairment in the working-age population worldwide. Various modes of photoreceptor cell death contribute to the development of DR, including apoptosis and autophagy. However, whether ferroptosis is involved in the pathogenesis of photoreceptor degeneration in DR is still unclear. High-glucose (HG)-stimulated 661W cells and diabetic mice models were used for in vitro and in vivo experiments, respectively. The levels of intracellular iron, glutathione (GSH), reactive oxygen species (ROS), lipid peroxidation (MDA), and ferroptosis-related proteins (GPX4, SLC7A11, ACSL4, FTH1, and NCOA4) were quantified to indicate ferroptosis. The effect of ferroptosis inhibition was also assessed. Our data showed the levels of iron, ROS, and MDA were enhanced and GSH concentration was reduced in HG-induced 661W cells and diabetic retinas. The expression of GPX4 and SLC7A11 was downregulated, while the expression of ACSL4, FTH1, and NCOA4 was upregulated in the 661W cells cultured under HG conditions and in the photoreceptor cells in diabetic mice. Furthermore, the administration of the ferroptosis inhibitor ferrostatin-1 (Fer-1) obviously alleviated ferroptosis-related changes in HG-cultured 661W cells and in retinal photoreceptor cells in diabetic mice. Taken together, our findings suggest that ferroptosis is involved in photoreceptor degeneration in the development of the early stages of DR.
Topics: Animals; Mice; Diabetes Mellitus, Experimental; Ferroptosis; Reactive Oxygen Species; Diabetic Retinopathy; 3,4-Methylenedioxyamphetamine; Glutathione; Iron; Transcription Factors
PubMed: 38069270
DOI: 10.3390/ijms242316946 -
ELife Oct 2023Mononuclear cells are involved in the pathogenesis of retinal diseases, including age-related macular degeneration (AMD). Here, we examined the mechanisms that underlie...
Mononuclear cells are involved in the pathogenesis of retinal diseases, including age-related macular degeneration (AMD). Here, we examined the mechanisms that underlie macrophage-driven retinal cell death. Monocytes were extracted from patients with AMD and differentiated into macrophages (hMdɸs), which were characterized based on proteomics, gene expression, and ex vivo and in vivo properties. Using bioinformatics, we identified the signaling pathway involved in macrophage-driven retinal cell death, and we assessed the therapeutic potential of targeting this pathway. We found that M2a hMdɸs were associated with retinal cell death in retinal explants and following adoptive transfer in a photic injury model. Moreover, M2a hMdɸs express several CCRI (C-C chemokine receptor type 1) ligands. Importantly, CCR1 was upregulated in Müller cells in models of retinal injury and aging, and CCR1 expression was correlated with retinal damage. Lastly, inhibiting CCR1 reduced photic-induced retinal damage, photoreceptor cell apoptosis, and retinal inflammation. These data suggest that hMdɸs, CCR1, and Müller cells work together to drive retinal and macular degeneration, suggesting that CCR1 may serve as a target for treating these sight-threatening conditions.
Topics: Humans; Animals; Retinal Degeneration; Ependymoglial Cells; Photoreceptor Cells; Retina; Macular Degeneration; Cell Death; Disease Models, Animal; Receptors, CCR1
PubMed: 37903056
DOI: 10.7554/eLife.81208 -
Stem Cells Translational Medicine Aug 2023Retinal pigment epithelium (RPE) is a critical cell monolayer forming the blood-retina-barrier (BRB) and a permeable bridge between the choriocapillaris and the retina.... (Review)
Review
Retinal pigment epithelium (RPE) is a critical cell monolayer forming the blood-retina-barrier (BRB) and a permeable bridge between the choriocapillaris and the retina. RPE is also crucial in maintaining photoreceptor function and for completing the visual cycle. Loss of the RPE is associated with the development of degenerative diseases like age-related macular degeneration (AMD). To treat diseases like AMD, pluripotent stem cell-derived RPE (pRPE) has been recently explored extensively as a regenerative module. pRPE like other ectodermal tissues requires specific lineage differentiation and long-term in vitro culturing for maturation. Therefore, understanding the differentiation process of RPE could be useful for stem cell-based RPE derivation. Developing pRPE-based transplants and delivering them into the subretinal space is another aspect that has garnered interest in the last decade. In this review, we discuss the basic strategies currently employed for stem cell-based RPE derivation, their delivery, and recent clinical studies related to pRPE transplantation in patients. We have also discussed a few limitations with in vitro RPE culture and potential solutions to overcome such problems which can be helpful in developing functional RPE tissue.
Topics: Humans; Retinal Pigment Epithelium; Retina; Macular Degeneration; Cell Differentiation; Pluripotent Stem Cells
PubMed: 37459045
DOI: 10.1093/stcltm/szad039 -
Journal of Neurochemistry Nov 2023GPR75 is an orphan G protein-coupled receptor for which there is currently limited information and its function in physiology and disease is only recently beginning to...
GPR75 is an orphan G protein-coupled receptor for which there is currently limited information and its function in physiology and disease is only recently beginning to emerge. This orphan receptor is expressed in the retina but its function in the eye is unknown. The earliest studies on GPR75 were conducted in the retina, where the receptor was first identified and cloned and mutations in the receptor were identified as a possible contributor to retinal degenerative disease. Despite these sporadic reports, the function of GPR75 in the retina and in retinal disease has yet to be explored. To assess whether GPR75 has a functional role in the retina, the retina of Gpr75 knockout mice was characterized. Knockout mice displayed a mild progressive retinal degeneration, which was accompanied by oxidative stress. The degeneration was because of the loss of both M-cone and S-cone photoreceptor cells. Housing mice under constant dark conditions reduced oxidative stress but did not prevent cone photoreceptor cell loss, indicating that oxidative stress is not a primary cause of the observed retinal degeneration. Studies here demonstrate an important role for GPR75 in maintaining the health of cone photoreceptor cells and that Gpr75 knockout mice can be used as a model to study cone photoreceptor cell loss.
Topics: Mice; Animals; Retinal Cone Photoreceptor Cells; Retinal Degeneration; Mice, Knockout; Retina; Mice, Inbred C57BL
PubMed: 37840219
DOI: 10.1111/jnc.15979 -
Annals of Medicine and Surgery (2012) Dec 2023Geographic atrophy (GA) is a progressive form of age-related macular degeneration characterized by the degeneration of retinal pigment epithelial cells and photoreceptor... (Review)
Review
Geographic atrophy (GA) is a progressive form of age-related macular degeneration characterized by the degeneration of retinal pigment epithelial cells and photoreceptor death. The dysregulation of the complement cascade has been implicated in GA progression. This review provides a comprehensive overview of the pathophysiology of age-related macular degeneration and GA, discusses current therapeutic options, and focuses on the recent breakthrough drug, pegcetacoplan (SYFOVRE). Pegcetacoplan is a complement inhibitor that selectively targets the C3 complement protein, effectively modulating complement activation. Clinical trials, including the OAKS and DERBY studies, have demonstrated the efficacy of SYFOVRE in reducing the growth of GA lesions compared to placebo. The FDA approval of SYFOVRE as the first and only definitive therapy for GA marks a significant milestone in the management of this debilitating condition. The review also explores potential future treatment strategies, including immune-modulating agents and ocular gene therapy. While SYFOVRE offers new hope for GA patients, further research is needed to evaluate its long-term benefits, safety profile, and optimal treatment regimens.
PubMed: 38098608
DOI: 10.1097/MS9.0000000000001466 -
Neural Regeneration Research Sep 2023Age-related macular degeneration is a major global cause of central visual impairment and severe vision loss. With an aging population, the already immense economic... (Review)
Review
Age-related macular degeneration is a major global cause of central visual impairment and severe vision loss. With an aging population, the already immense economic burden of costly anti-vascular endothelial growth factor treatment is likely to increase. In addition, current conventional treatment is only available for the late neovascular stage of age-related macular degeneration, and injections can come with potentially devastating complications, introducing the need for more economical and risk-free treatment. In recent years, exosomes, which are nano-sized extracellular vesicles of an endocytic origin, have shown immense potential as diagnostic biomarkers and in the therapeutic application, as they are bestowed with characteristics including an expansive cargo that closely resembles their parent cell and exceptional ability of intercellular communication and targeting neighboring cells. Exosomes are currently undergoing clinical trials for various conditions such as type 1 diabetes and autoimmune diseases; however, exosomes as a potential therapy for several retinal diseases have just begun to undergo scrutinizing investigation with little literature on age-related macular degeneration specifically. This article will focus on the limited literature available on exosome transplantation treatment in age-related macular degeneration animal models and in vitro cell cultures, as well as briefly identify future research directions. Current literature on exosome therapy using age-related macular degeneration rodent models includes laser retinal injury, N-methyl-N-nitrosourea, and royal college of surgeon models, which mimic inflammatory and degenerative aspects of age-related macular degeneration. These have shown promising results in preserving retinal function and morphology, as well as protecting photoreceptors from apoptosis. Exosomes from their respective cellular origins may also act by regulating the expression of various inflammatory cytokines, mRNAs, and proteins involved in photoreceptor degeneration pathways to exert a therapeutic effect. Various findings have also opened exciting prospects for the involvement of cargo components in remedial effects on the damaged macula or retina.
PubMed: 36926702
DOI: 10.4103/1673-5374.367835 -
Neural Regeneration Research Mar 2024Taurine is considered a non-essential amino acid because it is synthesized by most mammals. However, dietary intake of taurine may be necessary to achieve the... (Review)
Review
Taurine is considered a non-essential amino acid because it is synthesized by most mammals. However, dietary intake of taurine may be necessary to achieve the physiological levels required for the development, maintenance, and function of certain tissues. Taurine may be especially important for the retina. The concentration of taurine in the retina is higher than that in any other tissue in the body and taurine deficiency causes retinal oxidative stress, apoptosis, and degeneration of photoreceptors and retinal ganglion cells. Low plasma taurine levels may also underlie retinal degeneration in humans and therefore, taurine administration could exert retinal neuroprotective effects. Taurine has antioxidant, anti-apoptotic, immunomodulatory, and calcium homeostasis-regulatory properties. This review summarizes the role of taurine in retinal health and disease, where it appears that taurine may be a promising nutraceutical.
PubMed: 37721291
DOI: 10.4103/1673-5374.380820 -
Non-coding RNA Research Mar 2024Circular RNAs (circRNAs) is a fascinating covalently closed circular non-coding RNA that is abundantly present in the transcriptome of eukaryotic cells. Its versatile... (Review)
Review
Circular RNAs (circRNAs) is a fascinating covalently closed circular non-coding RNA that is abundantly present in the transcriptome of eukaryotic cells. Its versatile nature allows it to participate in a multitude of pathological and physiological processes within the organism. One of its crucial functions is acting as a microRNA sponge, modulating protein transcription levels, and forming interactions with essential RNA-binding proteins. Remarkably, circRNAs demonstrates a specific enrichment in various vital areas of the brain, including the cortex, hippocampus, white matter, and photoreceptor neurons, particularly in aging organisms. This intriguing characteristic has led scientists to explore its potential as a significant biological marker of neurodegeneration, offering promising insights into neurodegenerative diseases like Alzheimer's disease (AD). In AD, there has been an interesting observation of elevated levels of circRNAs in both peripheral blood and synaptic terminals of affected individuals. This intriguing finding raises the possibility that circRNAs may have a central role in the initiation and progression of AD. Notably, different categories of circRNAs, including HDAC9, HOMER1, Cwc27, Tulp4, and PTK2, have been implicated in driving the pathological changes associated with AD through diverse mechanisms. For instance, these circRNAs have been demonstrated to contribute to the accumulation of beta-amyloid, which is a hallmark characteristic of AD. Additionally, these circRNAs contribute to the excessive phosphorylation of tau protein, a phenomenon associated with neurofibrillary tangles, further exacerbating the disease. Moreover, they are involved in aggravating neuroinflammation, which is known to play a critical role in AD's pathogenesis. Lastly, these circRNAs can cause mitochondrial dysfunction, disrupting cellular energy production and leading to cognitive impairment. As researchers delve deeper into the intricate workings of circRNAs, they hope to unlock its full potential as a diagnostic tool and therapeutic target for neurodegenerative disorders, paving the way for innovative treatments and better management of such devastating conditions.
PubMed: 38125754
DOI: 10.1016/j.ncrna.2023.11.011 -
Eye (London, England) Aug 2023The importance of the visual system to birds for behaviours from feeding, mate choice, flying, navigation and determination of seasons, together with the presence of... (Review)
Review
The importance of the visual system to birds for behaviours from feeding, mate choice, flying, navigation and determination of seasons, together with the presence of photoreceptors in the retina, the pineal and the brain, render the avian visual system a particularly fruitful model for understanding of eye-brain interactions. In this review we will particularly focus on the pigeon, since here we have a brain stereotactically mapped and a genome fully sequenced, together with a particular bird, the homing pigeon, with remarkable ability to navigate over hundreds of miles and return to exactly the same roosting site with exceptional precision. We might denigrate the avian species by the term bird brained, but here are animals with phenomenal abilities to use their exceptional vision, their eagle eyedness, to best advantage.
Topics: Animals; Birds; Brain; Retina; Vision, Ocular; Photoreceptor Cells
PubMed: 37353509
DOI: 10.1038/s41433-023-02568-y