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Zaluski J, Bassetto M, Kiser PD, Tochtrop GP. Advances and therapeutic opportunities in visual cycle modulation. Prog Retin Eye Res 2025; 106:101360. [PMID: 40280538 PMCID: PMC12147667 DOI: 10.1016/j.preteyeres.2025.101360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 04/19/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025]
Abstract
The visual cycle is a metabolic pathway that enables continuous vision by regenerating the 11-cis-retinal chromophore for photoreceptors opsins. Although integral to normal visual function, the flux of retinoids through this cycle can contribute to a range of retinal pathologies, including Stargardt disease, age-related macular degeneration, and diabetic retinopathy. In such conditions, intermediates and byproducts of the visual cycle, such as bisretinoid components of lipofuscin, can accumulate, concomitant with cellular damage and eventual photoreceptor loss. This has inspired efforts to modulate the visual cycle, aiming to slow or prevent the formation of these toxic intermediates and thus preserve retinal structure and function. Over the past two decades, multiple strategies to modulate the visual cycle have emerged. These include both intrinsic approaches, targeting key enzymes, retinoid-binding proteins, or receptors within the pigment epithelium or photoreceptors (e.g., RPE65, CRBP1, and rhodopsin inhibitors/antagonists) and extrinsic strategies that indirectly alter retinoid availability within the retina (e.g., RBP4 antagonists). Many of these agents have shown promise in animal models of visual cycle-associated retinal diseases, reducing pathological changes, and improving retinal survival. Several have advanced into clinical studies, although none are currently FDA-approved. Challenges remain in optimizing drug specificity and duration of action while minimizing side effects such as nyctalopia. In this review, we comprehensively examine current and emerging visual cycle modulators, discuss their medicinal chemistry, mechanisms of action, efficacy in preclinical and clinical studies, and highlight future opportunities for drug discovery aimed at safely and effectively preserving vision through modulation of this biochemical pathway.
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Affiliation(s)
- Jordan Zaluski
- Department of Chemistry, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Marco Bassetto
- Department of Physiology and Biophysics, School of Medicine, University of California- Irvine, Irvine, CA, 92697, USA; Department of Ophthalmology, Gavin Herbert Eye Institute, Center for Translational Vision Research, School of Medicine, University of California- Irvine, Irvine, CA, 92697, USA; Research Service, VA Long Beach Healthcare System, Long Beach, CA, 90822, USA
| | - Philip D Kiser
- Department of Physiology and Biophysics, School of Medicine, University of California- Irvine, Irvine, CA, 92697, USA; Department of Ophthalmology, Gavin Herbert Eye Institute, Center for Translational Vision Research, School of Medicine, University of California- Irvine, Irvine, CA, 92697, USA; Research Service, VA Long Beach Healthcare System, Long Beach, CA, 90822, USA; Department of Clinical Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University of California - Irvine, Irvine, CA, 92697, USA.
| | - Gregory P Tochtrop
- Department of Chemistry, Case Western Reserve University, Cleveland, OH, 44106, USA.
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Nonarath HJT, Simpson SL, Slobodianuk TL, Tran H, Collery RF, Dinculescu A, Link BA. The USH3A causative gene clarin1 functions in Müller glia to maintain retinal photoreceptors. PLoS Genet 2025; 21:e1011205. [PMID: 40067805 PMCID: PMC11925288 DOI: 10.1371/journal.pgen.1011205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 03/20/2025] [Accepted: 02/04/2025] [Indexed: 03/19/2025] Open
Abstract
Mutations in CLRN1 cause Usher syndrome type IIIA (USH3A), an autosomal recessive disorder characterized by hearing and vision loss, and often accompanied by vestibular dysfunction. The identity of the cell types responsible for the pathology and mechanisms leading to vision loss in USH3A remains elusive. To address this, we employed CRISPR/Cas9 technology to delete a large region in the coding and untranslated (UTR) region of zebrafish clrn1. The retinas of clrn1 mutant larvae exhibited sensitivity to cell stress, along with age-dependent loss of function and degeneration in the photoreceptor layer. Investigation revealed disorganization in the outer retina in clrn1 mutants, including actin-based structures of the Müller glia and photoreceptor cells. To assess cell-specific contributions to USH3A pathology, we specifically re-expressed clrn1 in either Müller glia or photoreceptor cells. Müller glia re-expression of clrn1 prevented the elevated cell death observed in larval clrn1 mutant zebrafish exposed to high-intensity light. Notably, the degree of phenotypic rescue correlated with the level of Clrn1 re-expression. Surprisingly, high levels of Clrn1 expression enhanced cell death in both wild-type and clrn1 mutant animals. However, rod- or cone-specific Clrn1 re-expression did not reduce the extent of cell death. Taken together, our findings underscore three crucial insights. First, clrn1 mutant zebrafish exhibit key pathological features of USH3A; second, Clrn1 within Müller glia plays a pivotal role in photoreceptor maintenance, with its expression requiring controlled regulation; third, the reliance of photoreceptors on Müller glia suggests a structural support mechanism, possibly through direct interactions between Müller glia and photoreceptors mediated in part by Clrn1 protein.
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Affiliation(s)
- Hannah J. T. Nonarath
- Department Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Samantha L. Simpson
- Department of Ophthalmology and Vision Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Tricia L. Slobodianuk
- Department Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Hai Tran
- Department Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Ross F. Collery
- Department of Ophthalmology and Vision Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Astra Dinculescu
- Department of Ophthalmology, University of Florida, Gainesville, Florida, United States of America
| | - Brian A. Link
- Department Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
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Aliff HL, Crockett AB, Chrenek MA, Nickerson JM, Boatright JH, Tseytlin O, Johnson M, Bockius HG, Kuzak SG, Ramamurthy V. Accessible LED Lightbox for Light-induced Retinal Damage in Pigmented Mice. Invest Ophthalmol Vis Sci 2025; 66:49. [PMID: 39969479 PMCID: PMC11841687 DOI: 10.1167/iovs.66.2.49] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 01/14/2025] [Indexed: 02/20/2025] Open
Abstract
Purpose To design and validate a cost-effective and titratable system capable of light-induced photoreceptor dysfunction and damage in pigmented mice. Methods Two commonly used mouse strains in vision research, C57BL/6J and 129SVE mice, were exposed individually to varying light intensities in custom-designed boxes. Visual function was assessed by ERG, which was conducted two days prior, one day, and one week after light exposure. For morphological evaluation of photoreceptor health, we stained retinal sections with hematoxylin and eosin followed by light microscopy. Photoreceptor nuclei were quantified at equidistant points across the entire retina. Results C57BL/6J and 129SVE mice exhibited a significant reduction in visual function 1 day after exposure to light at varying light intensities from 10 to 60 klx for 4 hours. We observed a loss in visual function 1 day after exposure that correlated with the light intensity. The visual function did not recover even at 7 days after exposure. We observed loss of photoreceptor nuclei with regional differences in susceptibility to light damage, with the central retina being more affected than the periphery. Conclusions The lightbox system we developed effectively reduced visual function in pigmented animals after 4 hours of light exposure. Additionally, the system is flexible; the intensity and duration of light exposure can be adjusted to induce a desired level of light-induced photoreceptor dysfunction and damage.
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Affiliation(s)
- Hunter L. Aliff
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, West Virginia, United States
| | - Alexis B. Crockett
- Department of Neuroscience, West Virginia University, Morgantown, West Virginia, United States
| | - Micah A. Chrenek
- Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, United States
| | - John M. Nickerson
- Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, United States
| | - Jeffrey H. Boatright
- Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, United States
- Atlanta VA Center for Visual and Neurocognitive Rehabilitation, Decatur, Georgia, United States
| | - Oxana Tseytlin
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, West Virginia, United States
| | - Matthew Johnson
- Department of Physics and Astronomy, West Virginia University, Eberly College of Arts and Sciences, Morgantown, West Virginia, United States
| | - Hayley G. Bockius
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, West Virginia, United States
| | - Sierra G. Kuzak
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, West Virginia, United States
| | - Visvanathan Ramamurthy
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, West Virginia, United States
- Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, West Virginia, United States
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Guarascio R, Cheetham ME. Light as a Mediator of Acute and Chronic Retina Degeneration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1468:247-251. [PMID: 39930204 DOI: 10.1007/978-3-031-76550-6_41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
In age-related macula dystrophy (AMD) and some forms of inherited retinal dystrophies (IRDs), blindness is caused by the loss of photoreceptors and retinal pigment epithelium (RPE) cells. This process can be exacerbated by genetic and environmental risk factors, including exposure of the retina to bright light. Several light damage models have been developed and have proved to be powerful tools to study retinal degeneration. These models have enabled the investigation of common mechanisms of cell death and inflammation, as well as the identification of therapeutic targets and the assessment of potential new therapies against retinal degeneration. Here, we discuss the principal mechanisms of light-induced toxicity and highlight how this has been used in the development of therapeutic approaches to treat AMD and IRDs.
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Miranda-Benabarre C, Quijón PA, Lohrmann KB, Manríquez PH, Pulgar J, Quintanilla-Ahumada D, Davies TW, Widdicombe S, Jahnsen-Guzmán N, González C, Duarte C. Crustacean photoreceptor damage and recovery: Applying a novel scanning electronic microscopy protocol in artificial light studies. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 957:177561. [PMID: 39551210 DOI: 10.1016/j.scitotenv.2024.177561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/14/2024] [Accepted: 11/12/2024] [Indexed: 11/19/2024]
Abstract
Artificial light at night is a worldwide expanding form of pollution. Studies evaluating the effects of artificial light at night have often overlooked their impact on the photoreceptor, the basic functional structure of animals to absorb light. This is essential to understand the mechanisms by which this stressor may be impacting species. This study examined the photoreceptor (rhabdom) of two sandy beach crustaceans exhibiting different light tolerances at night: the amphipod Orchestoidea tuberculata and the isopod Tylos spinulosus. We developed a novel protocol to measure these species' photoreceptor areas and quantify the damage caused by artificial light at night using histological sections and scanning electron microscopy. In the isopod, a species naturally adapted to lower light intensities at night than the amphipod, the rhabdom surface was 20-times larger, and presented a tapetum, an adaptive feature found in species living in low light conditions. A brief exposure to artificial light caused 3-6 times more damage in the isopod's rhabdom. In fact, the light caused structural damage in the isopod's rhabdom but not in the amphipod's rhabdom, with no signs of recovery after 1 and 24 h. These findings suggest that the damage induced by artificial light at night on an organism's photoreceptors is more severe and persistent in species naturally adapted to lower light levels at night. Hence, this type of sensory ecological stressor may act as a novel selection pressure on these species, a concern with wide implications given the ubiquity among animals of the photoreceptor structure and its response to light.
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Affiliation(s)
- C Miranda-Benabarre
- Programa de Doctorado en Medicina de la Conservación, Universidad Andrés Bello, Santiago, Chile; Departamento de Ecología y Biodiversidad, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
| | - P A Quijón
- Coastal Ecology Laboratory, Department of Biology, University of Prince Edward Island, Charlottetown, PE, Canada
| | - K B Lohrmann
- Departamento de Biología Marina, Facultad de Ciencias del Mar, Universidad Católica del Norte, Coquimbo, Chile
| | - P H Manríquez
- Centro de Estudios Avanzados en Zonas Áridas (CEAZA), Coquimbo, Chile; Laboratorio de Ecología y Conducta de la Ontogenia Temprana (LECOT), Coquimbo, Chile
| | - J Pulgar
- Departamento de Ecología y Biodiversidad, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile; Centro de Investigación Marina Quintay (CIMARQ), Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
| | - D Quintanilla-Ahumada
- Programa de Doctorado en Medicina de la Conservación, Universidad Andrés Bello, Santiago, Chile; Departamento de Ecología y Biodiversidad, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile; Coastal Ecology Laboratory, Department of Biology, University of Prince Edward Island, Charlottetown, PE, Canada
| | - T W Davies
- School of Biological and Marine Sciences, University of Plymouth, Plymouth, Devon, UK
| | - S Widdicombe
- Plymouth Marine Laboratory, Prospect Place, West Hoe, Plymouth PL1 3DH, UK
| | - N Jahnsen-Guzmán
- Programa de Doctorado en Medicina de la Conservación, Universidad Andrés Bello, Santiago, Chile; Departamento de Ecología y Biodiversidad, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
| | - C González
- Escuela de Medicina Veterinaria, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
| | - C Duarte
- Departamento de Ecología y Biodiversidad, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile; Centro de Investigación Marina Quintay (CIMARQ), Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile.
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Tam BM, Burns P, Chiu CN, Moritz OL. Synchronized Photoactivation of T4K Rhodopsin Causes a Chromophore-Dependent Retinal Degeneration That Is Moderated by Interaction with Phototransduction Cascade Components. J Neurosci 2024; 44:e0453242024. [PMID: 39089885 PMCID: PMC11376340 DOI: 10.1523/jneurosci.0453-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/29/2024] [Accepted: 07/24/2024] [Indexed: 08/04/2024] Open
Abstract
Multiple mutations in the Rhodopsin gene cause sector retinitis pigmentosa in humans and a corresponding light-exacerbated retinal degeneration (RD) in animal models. Previously we have shown that T4K rhodopsin requires photoactivation to exert its toxic effect. Here we further investigated the mechanisms involved in rod cell death caused by T4K rhodopsin in mixed male and female Xenopus laevis In this model, RD was prevented by rearing animals in constant darkness but surprisingly also in constant light. RD was maximized by light cycles containing at least 1 h of darkness and 20 min of light exposure, light intensities >750 lux, and by a sudden light onset. Under conditions of frequent light cycling, RD occurred rapidly and synchronously, with massive shedding of ROS fragments into the RPE initiated within hours and subsequent death and phagocytosis of rod cell bodies. RD was minimized by reduced light levels, pretreatment with constant light, and gradual light onset. RD was prevented by genetic ablation of the retinal isomerohydrolase RPE65 and exacerbated by ablation of phototransduction components GNAT1, SAG, and GRK1. Our results indicate that photoactivated T4K rhodopsin is toxic, that cell death requires synchronized photoactivation of T4K rhodopsin, and that toxicity is mitigated by interaction with other rod outer segment proteins regardless of whether they participate in activation or shutoff of phototransduction. In contrast, RD caused by P23H rhodopsin does not require photoactivation of the mutant protein, as it was exacerbated by RPE65 ablation, suggesting that these phenotypically similar disorders may require different treatment strategies.
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Affiliation(s)
- Beatrice M Tam
- Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, British Columbia V5Z 3N9, Canada
| | - Paloma Burns
- Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, British Columbia V5Z 3N9, Canada
| | - Colette N Chiu
- Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, British Columbia V5Z 3N9, Canada
| | - Orson L Moritz
- Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, British Columbia V5Z 3N9, Canada
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Kaufmann M, Han Z. RPE melanin and its influence on the progression of AMD. Ageing Res Rev 2024; 99:102358. [PMID: 38830546 PMCID: PMC11260545 DOI: 10.1016/j.arr.2024.102358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 05/27/2024] [Indexed: 06/05/2024]
Abstract
OBJECTIVE The aim of this review article is to summarize the latest findings and current understanding of the origin of melanin in the retinal pigment epithelium (RPE), its function within the RPE, its role in the pathogenesis of age-related macular degeneration (AMD), its effect on retinal development, and its potential therapeutic benefit in the treatment of AMD. METHODS A comprehensive search of peer-reviewed journals was conducted using various combinations of key terms such as "melanin," "retinal pigment epithelium" or "RPE," "age-related macular degeneration" or AMD," "lipofuscin," "oxidative stress," and "albinism." Databases searched include PubMed, Scopus, Science Direct, and Google Scholar. 147 papers published between the years of 1957 and 2023 were considered with an emphasis on recent findings. SUMMARY OF FINDINGS AMD is thought to result from chronic oxidative stress within the RPE that results in cellular dysfunction, metabolic dysregulation, inflammation, and lipofuscin accumulation. Melanin functions as a photoscreener, free radical scavenger, and metal cation binding reservoir within the RPE. RPE melanin does not regenerate, and it undergoes degradation over time in response to chronic light exposure and oxidative stress. RPE melanin is important for retinal development and RPE function, and in the aging eye, melanin loss is associated with increased lipid peroxidation, inflammation, and the accumulation of toxic oxidized cellular products. Therefore, melanin-based treatments may serve to preserve RPE and retinal function in AMD. CONCLUSIONS The pathogenesis of AMD is not fully understood, but RPE dysfunction and melanin loss in response to chronic oxidative stress and inflammation are thought to be primary drivers of the disease. Due to melanin's antioxidative effects, melanin-based nanotechnology represents a promising avenue for the treatment of AMD.
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Affiliation(s)
- Mary Kaufmann
- University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
| | - Zongchao Han
- Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Pharmacoengineering & Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Bassetto M, Kolesnikov AV, Lewandowski D, Kiser JZ, Halabi M, Einstein DE, Choi EH, Palczewski K, Kefalov VJ, Kiser PD. Dominant role for pigment epithelial CRALBP in supplying visual chromophore to photoreceptors. Cell Rep 2024; 43:114143. [PMID: 38676924 PMCID: PMC11211020 DOI: 10.1016/j.celrep.2024.114143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/22/2024] [Accepted: 04/09/2024] [Indexed: 04/29/2024] Open
Abstract
Cellular retinaldehyde-binding protein (CRALBP) supports production of 11-cis-retinaldehyde and its delivery to photoreceptors. It is found in the retinal pigment epithelium (RPE) and Müller glia (MG), but the relative functional importance of these two cellular pools is debated. Here, we report RPE- and MG-specific CRALBP knockout (KO) mice and examine their photoreceptor and visual cycle function. Bulk visual chromophore regeneration in RPE-KO mice is 15-fold slower than in controls, accounting for their delayed rod dark adaptation and protection against retinal phototoxicity, whereas MG-KO mice have normal bulk visual chromophore regeneration and retinal light damage susceptibility. Cone pigment regeneration is significantly impaired in RPE-KO mice but mildly affected in MG-KO mice, disclosing an unexpectedly strong reliance of cone photoreceptors on the RPE-based visual cycle. These data reveal a dominant role for RPE-CRALBP in supporting rod and cone function and highlight the importance of RPE cell targeting for CRALBP gene therapies.
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Affiliation(s)
- Marco Bassetto
- Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, USA; Research Service, Tibor Rubin VA Long Beach Medical Center, Long Beach, CA 90822, USA; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California Irvine, Irvine, CA 92697, USA
| | - Alexander V Kolesnikov
- Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California Irvine, Irvine, CA 92697, USA
| | - Dominik Lewandowski
- Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California Irvine, Irvine, CA 92697, USA
| | - Jianying Z Kiser
- Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, USA; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California Irvine, Irvine, CA 92697, USA
| | - Maximilian Halabi
- Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, USA
| | - David E Einstein
- Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, USA; Research Service, Tibor Rubin VA Long Beach Medical Center, Long Beach, CA 90822, USA
| | - Elliot H Choi
- Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California Irvine, Irvine, CA 92697, USA
| | - Krzysztof Palczewski
- Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, USA; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California Irvine, Irvine, CA 92697, USA; Department of Chemistry, University of California Irvine, Irvine, CA 92697, USA; Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA 92697, USA
| | - Vladimir J Kefalov
- Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, USA; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California Irvine, Irvine, CA 92697, USA
| | - Philip D Kiser
- Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, USA; Research Service, Tibor Rubin VA Long Beach Medical Center, Long Beach, CA 90822, USA; Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of California Irvine, Irvine, CA 92697, USA; Department of Clinical Pharmacy Practice, University of California Irvine, Irvine, CA 92697, USA.
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9
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Anderson G, Borooah S, Megaw R, Bagnaninchi P, Weller R, McLeod A, Dhillon B. UVR and RPE - The Good, the Bad and the degenerate Macula. Prog Retin Eye Res 2024; 100:101233. [PMID: 38135244 DOI: 10.1016/j.preteyeres.2023.101233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 12/15/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023]
Abstract
Ultraviolet Radiation (UVR) has a well-established causative influence within the aetiology of conditions of the skin and the anterior segment of the eye. However, a grounded assessment of the role of UVR within conditions of the retina has been hampered by a historical lack of quantitative, and spectrally resolved, assessment of how UVR impacts upon the retina in terms congruent with contemporary theories of ageing. In this review, we sought to summarise the key findings of research investigating the connection between UVR exposure in retinal cytopathology while identifying necessary avenues for future research which can deliver a deeper understanding of UVR's place within the retinal risk landscape.
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Affiliation(s)
- Graham Anderson
- Centre for Regenerative Medicine, University of Edinburgh, Edinburgh BioQuarter, EH16 4UU, UK
| | - Shyamanga Borooah
- Viterbi Family Department of Ophthalmology, Shiley Eye Institute, UC San Diego, CA, 92093-0946, USA
| | - Roly Megaw
- Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, EH4 2XU, UK; Department of Clinical Ophthalmology, National Health Service Scotland, Edinburgh, EH3 9HA, UK
| | - Pierre Bagnaninchi
- Centre for Regenerative Medicine, University of Edinburgh, Edinburgh BioQuarter, EH16 4UU, UK; Robert O Curle Eyelab, Instute for Regeneration and Repair, Edinburgh BioQuarter, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Richard Weller
- Centre for Inflammation Research, University of Edinburgh, Edinburgh BioQuarter, EH16 4TJ, UK
| | - Andrew McLeod
- School of GeoSciences, University of Edinburgh, Crew Building, King's Buildings, EH9 3FF, UK
| | - Baljean Dhillon
- Department of Clinical Ophthalmology, National Health Service Scotland, Edinburgh, EH3 9HA, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh BioQuarter, EH16 4SB, UK; Robert O Curle Eyelab, Instute for Regeneration and Repair, Edinburgh BioQuarter, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK.
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10
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Nonarath HJT, Simpson SL, Slobodianuk TL, Collery RF, Dinculescu A, Link BA. The USH3A causative gene clarin1 functions in Müller glia to maintain retinal photoreceptors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.29.582878. [PMID: 38464015 PMCID: PMC10925332 DOI: 10.1101/2024.02.29.582878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Mutations in CLRN1 cause Usher syndrome type IIIA (USH3A), an autosomal recessive disorder characterized by hearing and vision loss, and often accompanied by vestibular balance issues. The identity of the cell types responsible for the pathology and mechanisms leading to vision loss in USH3A remains elusive. To address this, we employed CRISPR/Cas9 technology to delete a large region in the coding and untranslated (UTR) region of zebrafish clrn1. Retina of clrn1 mutant larvae exhibited sensitivity to cell stress, along with age-dependent loss of function and degeneration in the photoreceptor layer. Investigation revealed disorganization in the outer retina in clrn1 mutants, including actin-based structures of the Müller glia and photoreceptor cells. To assess cell-specific contributions to USH3A pathology, we specifically re-expressed clrn1 in either Müller glia or photoreceptor cells. Müller glia re-expression of clrn1 prevented the elevated cell death observed in larval clrn1 mutant zebrafish exposed to high-intensity light. Notably, the degree of phenotypic rescue correlated with the level of Clrn1 re-expression. Surprisingly, high levels of Clrn1 expression enhanced cell death in both wild-type and clrn1 mutant animals. However, rod- or cone-specific Clrn1 re-expression did not rescue the extent of cell death. Taken together, our findings underscore three crucial insights. First, clrn1 mutant zebrafish exhibit key pathological features of USH3A; second, Clrn1 within Müller glia plays a pivotal role in photoreceptor maintenance, with its expression requiring controlled regulation; third, the reliance of photoreceptors on Müller glia suggests a structural support mechanism, possibly through direct interactions between Müller glia and photoreceptors mediated in part by Clrn1 protein.
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Affiliation(s)
- Hannah J. T. Nonarath
- Department Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
| | - Samantha L. Simpson
- Department of Ophthalmology and Vision Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
| | - Tricia L. Slobodianuk
- Department Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
| | - Ross F. Collery
- Department of Ophthalmology and Vision Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
| | - Astra Dinculescu
- Department of Ophthalmology, University of Florida, Gainesville, Florida 32611
| | - Brian A. Link
- Department Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
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11
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Castiglione GM, Chiu YLI, Gutierrez EDA, Van Nynatten A, Hauser FE, Preston M, Bhattacharyya N, Schott RK, Chang BSW. Convergent evolution of dim light vision in owls and deep-diving whales. Curr Biol 2023; 33:4733-4740.e4. [PMID: 37776863 DOI: 10.1016/j.cub.2023.09.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 08/21/2023] [Accepted: 09/05/2023] [Indexed: 10/02/2023]
Abstract
Animals with enhanced dim-light sensitivity are at higher risk of light-induced retinal degeneration when exposed to bright light conditions.1,2,3,4 This trade-off is mediated by the rod photoreceptor sensory protein, rhodopsin (RHO), and its toxic vitamin A chromophore by-product, all-trans retinal.5,6,7,8 Rod arrestin (Arr-1) binds to RHO and promotes sequestration of excess all-trans retinal,9,10 which has recently been suggested as a protective mechanism against photoreceptor cell death.2,11 We investigated Arr-1 evolution in animals at high risk of retinal damage due to periodic bright-light exposure of rod-dominated retinas. Here, we find the convergent evolution of enhanced Arr-1/RHO all-trans-retinal sequestration in owls and deep-diving whales. Statistical analyses reveal a parallel acceleration of Arr-1 evolutionary rates in these lineages, which is associated with the introduction of a rare Arr-1 mutation (Q69R) into the RHO-Arr-1 binding interface. Using in vitro assays, we find that this single mutation significantly enhances RHO-all-trans-retinal sequestration by ∼30%. This functional convergence across 300 million years of evolutionary divergence suggests that Arr-1 and RHO may play an underappreciated role in the photoprotection of the eye, with potentially vast clinical significance.
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Affiliation(s)
- Gianni M Castiglione
- Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA; Department of Ophthalmology & Visual Sciences, Vanderbilt University, Nashville, TN 37232, USA; Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada; Department of Ecology & Evolutionary Biology, University of Toronto, Toronto, ON M5S 3B2, Canada; Evolutionary Studies, Vanderbilt University, Nashville, TN 37235, USA.
| | - Yan L I Chiu
- Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
| | - Eduardo de A Gutierrez
- Department of Ecology & Evolutionary Biology, University of Toronto, Toronto, ON M5S 3B2, Canada
| | - Alexander Van Nynatten
- Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada; Department of Biological Sciences, University of Toronto Scarborough, Toronto, ON M1C 1A4, Canada
| | - Frances E Hauser
- Department of Ecology & Evolutionary Biology, University of Toronto, Toronto, ON M5S 3B2, Canada; Department of Biological Sciences, University of Toronto Scarborough, Toronto, ON M1C 1A4, Canada
| | - Matthew Preston
- Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
| | - Nihar Bhattacharyya
- Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada; Institute of Ophthalmology, University College London, London EC1V 2PD, UK
| | - Ryan K Schott
- Department of Ecology & Evolutionary Biology, University of Toronto, Toronto, ON M5S 3B2, Canada; Department of Biology and Centre for Vision Research, York University, Toronto, ON M3J 1P3, Canada; Department of Vertebrate Zoology, National Museum of Natural History, Smithsonian Institution, Washington, DC 20560, USA
| | - Belinda S W Chang
- Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada; Department of Ecology & Evolutionary Biology, University of Toronto, Toronto, ON M5S 3B2, Canada.
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12
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Katada Y, Yoshida K, Serizawa N, Lee D, Kobayashi K, Negishi K, Okano H, Kandori H, Tsubota K, Kurihara T. Highly sensitive visual restoration and protection via ectopic expression of chimeric rhodopsin in mice. iScience 2023; 26:107716. [PMID: 37720108 PMCID: PMC10504486 DOI: 10.1016/j.isci.2023.107716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/22/2023] [Accepted: 08/22/2023] [Indexed: 09/19/2023] Open
Abstract
Photoreception requires amplification by mammalian rhodopsin through G protein activation, which requires a visual cycle. To achieve this in retinal gene therapy, we incorporated human rhodopsin cytoplasmic loops into Gloeobacter rhodopsin, thereby generating Gloeobacter and human chimeric rhodopsin (GHCR). In a murine model of inherited retinal degeneration, we induced retinal GHCR expression by intravitreal injection of a recombinant adeno-associated virus vector. Retinal explant and visual thalamus electrophysiological recordings, behavioral tests, and histological analysis showed that GHCR restored dim-environment vision and prevented the progression of retinal degeneration. Thus, GHCR may be a potent clinical tool for the treatment of retinal disorders.
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Affiliation(s)
- Yusaku Katada
- Laboratory of Photobiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
- Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Kazuho Yoshida
- Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Nagoya, Aichi 466-0061, Japan
| | - Naho Serizawa
- Laboratory of Photobiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
- Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
- Department of Nutritional Sciences, Toyo University, Kita-ku, Tokyo 115-8650, Japan
| | - Deokho Lee
- Laboratory of Photobiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
- Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Kenta Kobayashi
- Section of Viral Vector Development, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8585, Japan
| | - Kazuno Negishi
- Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Hideki Kandori
- Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Nagoya, Aichi 466-0061, Japan
| | - Kazuo Tsubota
- Tsubota Laboratory, Inc., Shinjuku-ku, Tokyo 160-0016, Japan
| | - Toshihide Kurihara
- Laboratory of Photobiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
- Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
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13
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McIlwaine G, Csincsik L, Coey R, Wang L, Fitzgerald D, Moffat J, Dubis AM, McDonnell G, Hughes S, Peto T, Lengyel I. Reduced Cone Density Is Associated with Multiple Sclerosis. OPHTHALMOLOGY SCIENCE 2023; 3:100308. [PMID: 37214765 PMCID: PMC10199246 DOI: 10.1016/j.xops.2023.100308] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/01/2023] [Accepted: 04/06/2023] [Indexed: 05/24/2023]
Abstract
Purpose Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system. Recent evidence suggests that degeneration of the inner layers of the retina occurs in MS. This study aimed to examine whether there are outer retinal changes in patients living with MS. Design This was a single center, cross-sectional study. Participants Sixteen patients with MS and 25 controls (volunteers without diagnosed MS) were recruited for the study. Methods We acquired volumetric spectral domain-OCT scans of the macula and a circular scan around the optic nerve head (ONH). We also captured adaptive optics (AO) images at 0° (centered on the foveola), 2°, 4°, and 6° temporal to the fovea. Main Outcome Measures We calculated the thickness of the different retinal layers in the macula and around the ONH using the inbuilt software of the OCT. We evaluated changes in cone photoreceptors by calculating cone density and spacing by the inbuilt AO automatic segmentation algorithm with manual correction. We compared patients with and without optic neuritis and controls. Results We found significant thinning of the inner retina and a thickening of the outer retina in the eye with a history of optic neuritis (eyes of patients with MS with a history of optic neuritis; mean difference [MD]: -11.13 ± 3.61 μm, P = 0.002 and MD: 2.86 ± 0.89 μm, P = 0.001; respectively). We did not observe changes in retinal layers without optic neuritis in eyes of patients with MS without a history of optic neuritis. However, regional differences were detected in the peripapillary retinal nerve fiber layer. Analyzing AO images revealed a significantly lower cone outer-segment density at all eccentricities in all patients compared with control eyes (P < 0.05), independent of optic neuritis history. Conclusions Our results showed that all MS cases were associated with decreased cone densities. Future longitudinal studies will help to elucidate whether this is a specific and sensitive method to detect and monitor the development and progression of MS. Financial Disclosures Proprietary or commercial disclosure may be found after the references.
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Affiliation(s)
- Gemma McIlwaine
- Wellcome Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
| | - Lajos Csincsik
- Wellcome Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
- Centre for Public Health, Queen’s University Belfast, Belfast, UK
| | - Rachel Coey
- Wellcome Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
| | - Luping Wang
- Wellcome Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
| | - Denise Fitzgerald
- Wellcome Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
| | - Jill Moffat
- Wellcome Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
| | - Adam M. Dubis
- UCL Global Business School for Health, University College London, London, UK
| | - Gavin McDonnell
- Department of Neurology, The Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK
| | - Stella Hughes
- Department of Neurology, The Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK
| | - Tunde Peto
- Centre for Public Health, Queen’s University Belfast, Belfast, UK
| | - Imre Lengyel
- Wellcome Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK
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14
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Markitantova Y, Simirskii V. Endogenous and Exogenous Regulation of Redox Homeostasis in Retinal Pigment Epithelium Cells: An Updated Antioxidant Perspective. Int J Mol Sci 2023; 24:10776. [PMID: 37445953 DOI: 10.3390/ijms241310776] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 06/22/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
The retinal pigment epithelium (RPE) performs a range of necessary functions within the neural layers of the retina and helps ensure vision. The regulation of pro-oxidative and antioxidant processes is the basis for maintaining RPE homeostasis and preventing retinal degenerative processes. Long-term stable changes in the redox balance under the influence of endogenous or exogenous factors can lead to oxidative stress (OS) and the development of a number of retinal pathologies associated with RPE dysfunction, and can eventually lead to vision loss. Reparative autophagy, ubiquitin-proteasome utilization, the repair of damaged proteins, and the maintenance of their conformational structure are important interrelated mechanisms of the endogenous defense system that protects against oxidative damage. Antioxidant protection of RPE cells is realized as a result of the activity of specific transcription factors, a large group of enzymes, chaperone proteins, etc., which form many signaling pathways in the RPE and the retina. Here, we discuss the role of the key components of the antioxidant defense system (ADS) in the cellular response of the RPE against OS. Understanding the role and interactions of OS mediators and the components of the ADS contributes to the formation of ideas about the subtle mechanisms in the regulation of RPE cellular functions and prospects for experimental approaches to restore RPE functions.
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Affiliation(s)
- Yuliya Markitantova
- Koltsov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
| | - Vladimir Simirskii
- Koltsov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
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15
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Bassetto M, Zaluski J, Li B, Zhang J, Badiee M, Kiser PD, Tochtrop GP. Tuning the Metabolic Stability of Visual Cycle Modulators through Modification of an RPE65 Recognition Motif. J Med Chem 2023; 66:8140-8158. [PMID: 37279401 PMCID: PMC10824489 DOI: 10.1021/acs.jmedchem.3c00461] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
In the eye, the isomerization of all-trans-retinal to 11-cis-retinal is accomplished by a metabolic pathway termed the visual cycle that is critical for vision. RPE65 is the essential trans-cis isomerase of this pathway. Emixustat, a retinoid-mimetic RPE65 inhibitor, was developed as a therapeutic visual cycle modulator and used for the treatment of retinopathies. However, pharmacokinetic liabilities limit its further development including: (1) metabolic deamination of the γ-amino-α-aryl alcohol, which mediates targeted RPE65 inhibition, and (2) unwanted long-lasting RPE65 inhibition. We sought to address these issues by more broadly defining the structure-activity relationships of the RPE65 recognition motif via the synthesis of a family of novel derivatives, which were tested in vitro and in vivo for RPE65 inhibition. We identified a potent secondary amine derivative with resistance to deamination and preserved RPE65 inhibitory activity. Our data provide insights into activity-preserving modifications of the emixustat molecule that can be employed to tune its pharmacological properties.
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Affiliation(s)
- Marco Bassetto
- Department of Physiology and Biophysics, School of Medicine, University of California - Irvine, Irvine, California 92697, United States
- Department of Ophthalmology, Gavin Herbert Eye Institute, Center for Translational Vision Research, School of Medicine, University of California - Irvine, Irvine, California 92697, United States
- Research Service, VA Long Beach Healthcare System, Long Beach, California 90822, United States
| | - Jordan Zaluski
- Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States
| | - Bowen Li
- Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States
| | - Jianye Zhang
- Department of Ophthalmology, Gavin Herbert Eye Institute, Center for Translational Vision Research, School of Medicine, University of California - Irvine, Irvine, California 92697, United States
| | - Mohsen Badiee
- Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States
| | - Philip D Kiser
- Department of Physiology and Biophysics, School of Medicine, University of California - Irvine, Irvine, California 92697, United States
- Department of Ophthalmology, Gavin Herbert Eye Institute, Center for Translational Vision Research, School of Medicine, University of California - Irvine, Irvine, California 92697, United States
- Department of Clinical Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University of California - Irvine, Irvine, California 92697, United States
- Research Service, VA Long Beach Healthcare System, Long Beach, California 90822, United States
| | - Gregory P Tochtrop
- Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States
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16
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Santos PF, Fazendeiro B, Luca FC, Ambrósio AF, Léger H. The NDR/LATS protein kinases in neurobiology: Key regulators of cell proliferation, differentiation and migration in the ocular and central nervous system. Eur J Cell Biol 2023; 102:151333. [PMID: 37327741 DOI: 10.1016/j.ejcb.2023.151333] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 06/07/2023] [Accepted: 06/09/2023] [Indexed: 06/18/2023] Open
Abstract
Nuclear Dbf2-related (NDR) kinases are a subgroup of evolutionarily conserved AGC protein kinases that regulate various aspects of cell growth and morphogenesis. There are 4 NDR protein kinases in mammals, LATS1, LATS2 and STTK8/NDR1, STK38L/NDR2 protein kinases. LATS1 and 2 are core components of the well-studied Hippo pathway, which play a critical role in the regulation of cell proliferation, differentiation, and cell migration via YAP/TAZ transcription factor. The Hippo pathways play an important role in nervous tissue development and homeostasis, especially with regard to the central nervous system (CNS) and the ocular system. The ocular system is a very complex system generated by the interaction in a very tightly coordinated manner of numerous and diverse developing tissues, such as, but not limited to choroidal and retinal blood vessels, the retinal pigmented epithelium and the retina, a highly polarized neuronal tissue. The retina development and maintenance require precise and coordinated regulation of cell proliferation, cell death, migration, morphogenesis, synaptic connectivity, and balanced homeostasis. This review highlights the emerging roles of NDR1 and NDR2 kinases in the regulation of retinal/neuronal function and homeostasis via a noncanonical branch of the Hippo pathway. We highlight a potential role of NDR1 and NDR2 kinases in regulating neuronal inflammation and as potential therapeutic targets for the treatment of neuronal diseases.
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Affiliation(s)
- Paulo F Santos
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University Coimbra, Azinhaga Santa Comba, Celas, 3000-548 Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), Faculty of Medicine, University Coimbra, Rua Larga, 3004-504 Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal; Department of Life Sciences, University Coimbra, CC Martim de Freitas, 3000-456 Coimbra, Portugal
| | - Beatriz Fazendeiro
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University Coimbra, Azinhaga Santa Comba, Celas, 3000-548 Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), Faculty of Medicine, University Coimbra, Rua Larga, 3004-504 Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
| | - Francis C Luca
- Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, United States
| | - António Francisco Ambrósio
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University Coimbra, Azinhaga Santa Comba, Celas, 3000-548 Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), Faculty of Medicine, University Coimbra, Rua Larga, 3004-504 Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal; Association for Innovation and Biomedical Research on Light and Image (AIBILI), Azinhaga Santa Comba, Celas, 3000-548 Coimbra, Portugal
| | - Hélène Léger
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University Coimbra, Azinhaga Santa Comba, Celas, 3000-548 Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), Faculty of Medicine, University Coimbra, Rua Larga, 3004-504 Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.
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17
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Polyunsaturated Lipids in the Light-Exposed and Prooxidant Retinal Environment. Antioxidants (Basel) 2023; 12:antiox12030617. [PMID: 36978865 PMCID: PMC10044808 DOI: 10.3390/antiox12030617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/26/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
The retina is an oxidative stress-prone tissue due to high content of polyunsaturated lipids, exposure to visible light stimuli in the 400–480 nm range, and high oxygen availability provided by choroidal capillaries to support oxidative metabolism. Indeed, lipids’ peroxidation and their conversion into reactive species promoting inflammation have been reported and connected to retinal degenerations. Here, we review recent evidence showing how retinal polyunsaturated lipids, in addition to oxidative stress and damage, may counteract the inflammatory response triggered by blue light-activated carotenoid derivatives, enabling long-term retina operation despite its prooxidant environment. These two aspects of retinal polyunsaturated lipids require tight control over their synthesis to avoid overcoming their protective actions by an increase in lipid peroxidation due to oxidative stress. We review emerging evidence on different transcriptional control mechanisms operating in retinal cells to modulate polyunsaturated lipid synthesis over the life span, from the immature to the ageing retina. Finally, we discuss the antioxidant role of food nutrients such as xanthophylls and carotenoids that have been shown to empower retinal cells’ antioxidant responses and counteract the adverse impact of prooxidant stimuli on sight.
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18
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Sirés A, Pazo-González M, López-Soriano J, Méndez A, de la Rosa EJ, de la Villa P, Comella JX, Hernández-Sánchez C, Solé M. The Absence of FAIM Leads to a Delay in Dark Adaptation and Hampers Arrestin-1 Translocation upon Light Reception in the Retina. Cells 2023; 12:cells12030487. [PMID: 36766830 PMCID: PMC9914070 DOI: 10.3390/cells12030487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/14/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
The short and long isoforms of FAIM (FAIM-S and FAIM-L) hold important functions in the central nervous system, and their expression levels are specifically enriched in the retina. We previously described that Faim knockout (KO) mice present structural and molecular alterations in the retina compatible with a neurodegenerative phenotype. Here, we aimed to study Faim KO retinal functions and molecular mechanisms leading to its alterations. Electroretinographic recordings showed that aged Faim KO mice present functional loss of rod photoreceptor and ganglion cells. Additionally, we found a significant delay in dark adaptation from early adult ages. This functional deficit is exacerbated by luminic stress, which also caused histopathological alterations. Interestingly, Faim KO mice present abnormal Arrestin-1 redistribution upon light reception, and we show that Arrestin-1 is ubiquitinated, a process that is abrogated by either FAIM-S or FAIM-L in vitro. Our results suggest that FAIM assists Arrestin-1 light-dependent translocation by a process that likely involves ubiquitination. In the absence of FAIM, this impairment could be the cause of dark adaptation delay and increased light sensitivity. Multiple retinal diseases are linked to deficits in photoresponse termination, and hence, investigating the role of FAIM could shed light onto the underlying mechanisms of their pathophysiology.
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Affiliation(s)
- Anna Sirés
- Cell Signaling and Apoptosis Group, Vall d’Hebron Institute of Research (VHIR), 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, 28029 Madrid, Spain
- Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain
| | - Mateo Pazo-González
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas (CSIC), 28040 Madrid, Spain
- Department of Systems Biology, Facultad de Medicina, Universidad de Alcalá, 28871 Alcalá de Henares, Spain
| | - Joaquín López-Soriano
- Cell Signaling and Apoptosis Group, Vall d’Hebron Institute of Research (VHIR), 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, 28029 Madrid, Spain
- Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain
| | - Ana Méndez
- Department of Physiological Sciences, School of Medicine, Campus Universitari de Bellvitge, University of Barcelona, 08907 Barcelona, Spain
- Institut de Neurociències, Campus Universitari de Bellvitge, University of Barcelona, 08907 Barcelona, Spain
- Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Campus Universitari de Bellvitge, University of Barcelona, 08907 Barcelona, Spain
| | - Enrique J. de la Rosa
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas (CSIC), 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, 28029 Madrid, Spain
| | - Pedro de la Villa
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas (CSIC), 28040 Madrid, Spain
- Department of Systems Biology, Facultad de Medicina, Universidad de Alcalá, 28871 Alcalá de Henares, Spain
| | - Joan X. Comella
- Cell Signaling and Apoptosis Group, Vall d’Hebron Institute of Research (VHIR), 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, 28029 Madrid, Spain
- Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain
| | - Catalina Hernández-Sánchez
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas (CSIC), 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, 28029 Madrid, Spain
| | - Montse Solé
- Cell Signaling and Apoptosis Group, Vall d’Hebron Institute of Research (VHIR), 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, 28029 Madrid, Spain
- Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain
- Correspondence:
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19
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Lu C, Li S, Jin M. Rapamycin Inhibits Light-Induced Necrosome Activation Occurring in Wild-Type, but not RPE65-Null, Mouse Retina. Invest Ophthalmol Vis Sci 2022; 63:19. [PMID: 36534385 PMCID: PMC9769341 DOI: 10.1167/iovs.63.13.19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Purpose Both photodamage and aberrant visual cycle contribute to disease progress of many retinal degenerative disorders, whereas the signaling pathways causing photoreceptor death remain unclear. Here we investigated the effects of intense photo-stress on (1) necrosome activation in wild-type and RPE65-null mice, (2) interaction of p62/Sequestosome-1 with the necrosome proteins, and (3) the effects of rapamycin on photodamage-induced necrosome activation and retinal degeneration in wild-type mice. Methods Dark-adapted rd12 mice and 129S2/Sv mice with or without rapamycin treatment were exposed to 15,000 lux light for different times. Expression levels and subcellular localization of proteins were determined through immunoblot and immunohistochemical analyses. Cone sheaths were stained with peanut agglutinin. Correlation between photoreceptor degeneration and receptor-interacting protein kinase-1 (RIPK1) expression was assessed with Spearman's correlation analysis. Protein-protein interaction was analyzed by immunoprecipitation. Results Intense light caused rod and cone degeneration accompanied by a significant increase in RIPK1-RIPK3 expressions, mixed lineage kinase domain-like protein phosphorylation, damage-associated molecular patterns protein release, and inflammatory responses in wild-type mouse retina. The same intense light did not induce the necrosome activation in rd12 retina, but it did in rd12 mice that received 9-cis-retinal supply. RIPK1 expression levels are positively correlated with the degrees of rod and cone degeneration. Photodamage upregulated expression and interaction of the p62 autophagosome cargo protein with the necrosome proteins, whereas rapamycin treatment attenuated the light-induced necrosome activation and photoreceptor degeneration. Conclusions Necrosome activation contributed to photodamage-induced rod and cone degeneration. The visual cycle and autophagy are the important therapeutic targets to alleviate light-induced retinal necroptosis.
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Affiliation(s)
- Chunfeng Lu
- Neuroscience Center of Excellence, Louisiana State University School of Medicine, LSU Health New Orleans, New Orleans, Louisiana, United States
| | - Songhua Li
- Neuroscience Center of Excellence, Louisiana State University School of Medicine, LSU Health New Orleans, New Orleans, Louisiana, United States
| | - Minghao Jin
- Neuroscience Center of Excellence, Louisiana State University School of Medicine, LSU Health New Orleans, New Orleans, Louisiana, United States,Department of Ophthalmology, Louisiana State University School of Medicine, LSU Health New Orleans, New Orleans, Louisiana, United States
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20
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Ardourel M, Ranchon-Cole I, Pâris A, Felgerolle C, Acar N, Lesne F, Briault S, Perche O. FMR protein: Evidence of an emerging role in retinal aging? Exp Eye Res 2022; 225:109282. [PMID: 36265576 DOI: 10.1016/j.exer.2022.109282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/05/2022] [Accepted: 10/11/2022] [Indexed: 12/29/2022]
Abstract
Aging is a multifactorial process that affects the entire organism by cumulative alterations. Visual function impairments that go along with aging are commonly observed, causing lower visual acuity, lower contrast sensitivity, and impaired dark adaptation. Electroretinogram analysis revealed that the amplitudes of rod- and cone-mediated responses are reduced in aged mice and humans. Reports suggested that age-related changes observed in both rod and cone photoreceptor functionality were linked to oxidative stress regulation or free radical production homeostasis. Interestingly, several recent reports linked the fragile X mental retardation protein (FMRP) cellular activity with oxidative stress regulation in several tissue including brain tissue where FMRP participates to the response to stress via protein translation in neurite or is involved in free radical production and abnormal glutathione homeostasis. Based on these recent literatures, we raised the question about the effect of FMRP absence in the aging retina of Fmr1-/y compared to their WT littermates. Indeed, up to now, only young or adult mice (<6 months) were investigated and have shown a specific retinal phenotype. Herein, we demonstrated that Fmr1-/y mice do not present the aging effect on retinal function observed in WT littermates since ERG a- and b-waves amplitudes as well as oscillatory potentials amplitudes were not collapsed with age (12/18 months old). Absence of FMRP and its consequences seem to protect the retina against aging effect, rising a pivotal role of FMRP in retinal aging process.
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Affiliation(s)
- M Ardourel
- UMR7355, CNRS, Orléans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orléans, 3b rue de la Ferollerie, 45071, Orléans, Cedex 2, France
| | - I Ranchon-Cole
- Université Clermont Auvergne, CHU Clermont-Ferrand, Inserm, Neuro-Dol, F-63000, Clermont-Ferrand, France
| | - A Pâris
- UMR7355, CNRS, Orléans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orléans, 3b rue de la Ferollerie, 45071, Orléans, Cedex 2, France
| | - C Felgerolle
- UMR7355, CNRS, Orléans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orléans, 3b rue de la Ferollerie, 45071, Orléans, Cedex 2, France
| | - N Acar
- Eye and Nutrition Research Group, Centre des Sciences du Goût et de l'Alimentation, CNRS, INRAE, Institut Agro, Université Bourgogne Franche-Comté, 21000, Dijon, France
| | - F Lesne
- Genetic Department, Regional Hospital, 14 Avenue de l'hôpital, 45100, Orléans, France
| | - S Briault
- UMR7355, CNRS, Orléans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orléans, 3b rue de la Ferollerie, 45071, Orléans, Cedex 2, France; Genetic Department, Regional Hospital, 14 Avenue de l'hôpital, 45100, Orléans, France
| | - O Perche
- UMR7355, CNRS, Orléans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orléans, 3b rue de la Ferollerie, 45071, Orléans, Cedex 2, France; Genetic Department, Regional Hospital, 14 Avenue de l'hôpital, 45100, Orléans, France.
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21
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The novel visual cycle inhibitor (±)-RPE65-61 protects retinal photoreceptors from light-induced degeneration. PLoS One 2022; 17:e0269437. [PMID: 36227868 PMCID: PMC9560169 DOI: 10.1371/journal.pone.0269437] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 05/23/2022] [Indexed: 11/25/2022] Open
Abstract
The visual cycle refers to a series of biochemical reactions of retinoids in ocular tissues and supports the vision in vertebrates. The visual cycle regenerates visual pigments chromophore, 11-cis-retinal, and eliminates its toxic byproducts from the retina, supporting visual function and retinal neuron survival. Unfortunately, during the visual cycle, when 11-cis-retinal is being regenerated in the retina, toxic byproducts, such as all-trans-retinal and bis-retinoid is N-retinylidene-N-retinylethanolamine (A2E), are produced, which are proposed to contribute to the pathogenesis of the dry form of age-related macular degeneration (AMD). The primary biochemical defect in Stargardt disease (STGD1) is the accelerated synthesis of cytotoxic lipofuscin bisretinoids, such as A2E, in the retinal pigment epithelium (RPE) due to mutations in the ABCA4 gene. To prevent all-trans-retinal-and bisretinoid-mediated retinal degeneration, slowing down the retinoid flow by modulating the visual cycle with a small molecule has been proposed as a therapeutic strategy. The present study describes RPE65-61, a novel, non-retinoid compound, as an inhibitor of RPE65 (a key enzyme in the visual cycle), intended to modulate the excessive activity of the visual cycle to protect the retina from harm degenerative diseases. Our data demonstrated that (±)-RPE65-61 selectively inhibited retinoid isomerase activity of RPE65, with an IC50 of 80 nM. Furthermore, (±)-RPE65-61 inhibited RPE65 via an uncompetitive mechanism. Systemic administration of (±)-RPE65-61 in mice resulted in slower chromophore regeneration after light bleach, confirming in vivo target engagement and visual cycle modulation. Concomitant protection of the mouse retina from high-intensity light damage was also observed. Furthermore, RPE65-61 down-regulated the cyclic GMP-AMP synthase stimulator of interferon genes (cGAS-STING) pathway, decreased the inflammatory factor, and attenuated retinal apoptosis caused by light-induced retinal damage (LIRD), which led to the preservation of the retinal function. Taken together, (±)-RPE65-61 is a potent visual cycle modulator that may provide a neuroprotective therapeutic benefit for patients with STGD and AMD.
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22
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Langouët M, Jolicoeur C, Javed A, Mattar P, Gearhart MD, Daiger SP, Bertelsen M, Tranebjærg L, Rendtorff ND, Grønskov K, Jespersgaard C, Chen R, Sun Z, Li H, Alirezaie N, Majewski J, Bardwell VJ, Sui R, Koenekoop RK, Cayouette M. Mutations in BCOR, a co-repressor of CRX/OTX2, are associated with early-onset retinal degeneration. SCIENCE ADVANCES 2022; 8:eabh2868. [PMID: 36070393 PMCID: PMC9451151 DOI: 10.1126/sciadv.abh2868] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 07/21/2022] [Indexed: 06/10/2023]
Abstract
Many transcription factors regulating the production, survival, and function of photoreceptor cells have been identified, but little is known about transcriptional co-regulators in retinal health and disease. Here, we show that BCL6 co-repressor (BCOR), a Polycomb repressive complex 1 factor mutated in various cancers, is involved in photoreceptor degenerative diseases. Using proteomics and transcription assays, we report that BCOR interacts with the transcription factors CRX and OTX2 and reduces their ability to activate the promoters of photoreceptor-specific genes. CUT&RUN sequencing further shows that BCOR shares genome-wide binding profiles with CRX/OTX2, consistent with a general co-repression activity. We also identify missense mutations in human BCOR in five families that have no evidence of cancer but present severe early-onset X-linked retinal degeneration. Last, we show that the human BCOR mutants cause degeneration when expressed in the mouse retina and have enhanced repressive activity on OTX2. These results uncover a role for BCOR in photoreceptors in both health and disease.
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Affiliation(s)
- Maéva Langouët
- Cellular Neurobiology Research Unit, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
| | - Christine Jolicoeur
- Cellular Neurobiology Research Unit, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
| | - Awais Javed
- Cellular Neurobiology Research Unit, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
| | - Pierre Mattar
- Cellular Neurobiology Research Unit, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
| | - Micah D. Gearhart
- Department of Genetics, Cell Biology and Development, Development Biology Center, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Stephen P. Daiger
- EHGED Department, Human Genetics Center, School of Public Health, University of Texas HSC, Houston, TX 77030, USA
| | - Mette Bertelsen
- Department of Clinical Genetics, Rigshospitalet, The Kennedy Centre, Copenhagen, Denmark
- Department of Ophthalmology, Rigshospitalet, The Kennedy Centre, Glostrup, Denmark
| | - Lisbeth Tranebjærg
- Department of Clinical Genetics, Rigshospitalet, The Kennedy Centre, Copenhagen, Denmark
- Institute of Clinical Medicine, University of Copenhagen, Denmark
| | - Nanna D. Rendtorff
- Department of Clinical Genetics, Rigshospitalet, The Kennedy Centre, Copenhagen, Denmark
| | - Karen Grønskov
- Department of Clinical Genetics, Rigshospitalet, The Kennedy Centre, Copenhagen, Denmark
| | - Catherine Jespersgaard
- Department of Clinical Genetics, Rigshospitalet, The Kennedy Centre, Copenhagen, Denmark
| | - Rui Chen
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Zixi Sun
- Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Hui Li
- Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Najmeh Alirezaie
- Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Jacek Majewski
- Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Vivian J. Bardwell
- Department of Genetics, Cell Biology and Development, Development Biology Center, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Ruifang Sui
- Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Robert K. Koenekoop
- Departments of Pediatric Surgery, Human Genetics, Adult Ophthalmology and the McGill Ocular Genetics Laboratory, McGill University Health Center Research Institute, Montreal, QC, Canada
| | - Michel Cayouette
- Cellular Neurobiology Research Unit, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
- Department of Medicine, Université de Montréal, Montreal, QC, Canada
- Department of Anatomy and Cell Biology, Division of Experimental Medicine, McGill University, Montreal, QC, Canada
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23
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Wang J, Tao Z, Deng H, Cui Y, Xu Z, Lyu Q, Zhao J. Therapeutic implications of nanodrug and tissue engineering for retinal pigment epithelium-related diseases. NANOSCALE 2022; 14:5657-5677. [PMID: 35352082 DOI: 10.1039/d1nr08337f] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The retinal pigment epithelium (RPE), as a single layer of cells that performs multiple functions posteriorly in the eye, is a promising target site for the prevention and treatment of several clinical diseases, including proliferative diabetic retinopathy, age-related macular degeneration, chorionic neovascularization, and retinitis pigmentosa. In recent decades, several nanodrug delivery platforms and tissue-engineered RPE have been widely developed to treat RPE-related diseases. This work summarizes the recent advances in nanoplatforms and tissue engineering scaffolds developed in these fields. The diseases associated with pathological RPE and their common therapy strategies are first introduced. Then, the recent progress made with a variety of drug delivery systems is presented, with an emphasis on the modification strategies of nanomaterials for targeted delivery. Tissue engineering-mediated RPE transplantation for treating these diseases is subsequently described. Finally, the clinical translation challenges in these fields are discussed in depth. This article will offer readers a better understanding of emerging nanotechnology and tissue engineering related to the treatment of RPE-related diseases and could facilitate their widespread use in experiments in vivo and in clinical applications.
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Affiliation(s)
- Jiao Wang
- Shenzhen Eye Hospital, Shenzhen Eye Institute, Shenzhen Eye Hospital affiliated to Jinan University, School of Optometry, Shenzhen University, Shenzhen 518000, China.
| | - Zhengyang Tao
- Shenzhen Eye Hospital, Shenzhen Eye Institute, Shenzhen Eye Hospital affiliated to Jinan University, School of Optometry, Shenzhen University, Shenzhen 518000, China.
| | - Hongwei Deng
- Shenzhen Eye Hospital, Shenzhen Eye Institute, Shenzhen Eye Hospital affiliated to Jinan University, School of Optometry, Shenzhen University, Shenzhen 518000, China.
| | - Yubo Cui
- Department of Ophthalmology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China.
| | - Zhirong Xu
- Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Qinghua Lyu
- Shenzhen Eye Hospital, Shenzhen Eye Institute, Shenzhen Eye Hospital affiliated to Jinan University, School of Optometry, Shenzhen University, Shenzhen 518000, China.
- Institute of Microscale Optoelectronics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China
| | - Jun Zhao
- Department of Ophthalmology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China.
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Tmem138 is localized to the connecting cilium essential for rhodopsin localization and outer segment biogenesis. Proc Natl Acad Sci U S A 2022; 119:e2109934119. [PMID: 35394880 PMCID: PMC9169668 DOI: 10.1073/pnas.2109934119] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The connecting cilium (CC) of the photoreceptor provides the only route for the trafficking of the outer segment (OS) proteins. Failure of OS protein transport causes degenerative photoreceptor diseases, including retinitis pigmentosa. We demonstrate that Tmem138, a protein linked to ciliopathy, is localized to the photoreceptor CC. Germline deletion of Tmem138 abolished OS morphogenesis, followed by rapid photoreceptor degeneration. Tmem138 interacts with rhodopsin and two additional CC compartment proteins, Ahi1 and Tmem231, likely forming a membrane complex to facilitate trafficking of rhodopsin and other OS-bound proteins across the CC. The study thus implicates a new line of regulation on the delivery of OS proteins through interactions with CC membrane complex(es) and provides insights into photoreceptor ciliopathy diseases. Photoreceptor connecting cilium (CC) is structurally analogous to the transition zone (TZ) of primary cilia and gates the molecular trafficking between the inner and the outer segment (OS). Retinal dystrophies with underlying CC defects are manifested in a broad array of syndromic conditions known as ciliopathies as well as nonsyndromic retinal degenerations. Despite extensive studies, many questions remain in the mechanism of protein trafficking across the photoreceptor CC. Here, we genetically inactivated mouse Tmem138, a gene encoding a putative transmembrane protein localized to the ciliary TZ and linked to ciliopathies. Germline deletion of Tmem138 abolished OS morphogenesis, followed by rapid photoreceptor degeneration. Tmem138 was found localized to the photoreceptor CC and was required for localization of Ahi1 to the distal subdomain of the CC. Among the examined set of OS proteins, rhodopsin was mislocalized throughout the mutant cell body prior to OS morphogenesis. Ablation of Tmem138 in mature rods recapitulated the molecular changes in the germline mutants, causing failure of disc renewal and disintegration of the OS. Furthermore, Tmem138 interacts reciprocally with rhodopsin and a related protein Tmem231, and the ciliary localization of the latter was also altered in the mutant photoreceptors. Taken together, these results suggest a crucial role of Tmem138 in the functional organization of the CC, which is essential for rhodopsin localization and OS biogenesis.
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25
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Kaidzu S, Okuno T, Tanito M, Ohira A. Structural and Functional Change in Albino Rat Retina Induced by Various Visible Light Wavelengths. Int J Mol Sci 2021; 23:309. [PMID: 35008736 PMCID: PMC8745104 DOI: 10.3390/ijms23010309] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/24/2021] [Accepted: 12/25/2021] [Indexed: 11/16/2022] Open
Abstract
The effects of visible light, from short to long wavelengths, on the retina were investigated functionally and histologically. The left eyes of Sprague-Dawley albino rats (6-weeks old, n = 6 for each wavelength) were exposed to seven narrow-band wavelengths (central wavelengths, 421, 441, 459, 501, 541, 581, and 615 nm) with bandwidths of 16 to 29 nm (half bandwidth, ±8-14.5 nm) using a xenon lamp source with bandpass filters at the retinal radiant exposures of 340 and 680 J/cm2. The right unexposed eyes served as controls. Seven days after exposure, flash electroretinograms (ERGs) were recorded, and the outer nuclear layer (ONL) thickness was measured. Compared to the unexposed eyes, significant reductions in the a- and b-wave ERG amplitudes were seen in eyes exposed to 460-nm or shorter wavelengths of light. The ONL thickness near the optic nerve head also tended to decrease with exposure to shorter wavelengths. The decreased ERG amplitudes and ONL thicknesses were most prominent in eyes exposed to 420-nm light at both radiant exposures. When the wavelengths were the same, the higher the amount of radiant exposure and the stronger the damage. Compared to the unexposed eyes, the a- and b-waves did not decrease significantly in eyes exposed to 500-nm or longer wavelength light. The results indicate that the retinal damage induced by visible light observed in albino rats depends on the wavelength and energy level of the exposed light.
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Affiliation(s)
- Sachiko Kaidzu
- Department of Ophthalmology, Faculty of Medicine, Shimane University, Izumo 693-8501, Shimane, Japan; (T.O.); (M.T.); (A.O.)
| | - Tsutomu Okuno
- Department of Ophthalmology, Faculty of Medicine, Shimane University, Izumo 693-8501, Shimane, Japan; (T.O.); (M.T.); (A.O.)
- Occupational Ergonomics Research Group, National Institute of Occupational Safety and Health, Tama-ku, Kawasaki 214-8585, Kanagawa, Japan
| | - Masaki Tanito
- Department of Ophthalmology, Faculty of Medicine, Shimane University, Izumo 693-8501, Shimane, Japan; (T.O.); (M.T.); (A.O.)
| | - Akihiro Ohira
- Department of Ophthalmology, Faculty of Medicine, Shimane University, Izumo 693-8501, Shimane, Japan; (T.O.); (M.T.); (A.O.)
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26
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Miralles de Imperial-Ollero JA, Gallego-Ortega A, Ortín-Martínez A, Villegas-Pérez MP, Valiente-Soriano FJ, Vidal-Sanz M. Animal Models of LED-Induced Phototoxicity. Short- and Long-Term In Vivo and Ex Vivo Retinal Alterations. Life (Basel) 2021; 11:life11111137. [PMID: 34833013 PMCID: PMC8617611 DOI: 10.3390/life11111137] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 12/26/2022] Open
Abstract
Phototoxicity animal models have been largely studied due to their degenerative communalities with human pathologies, e.g., age-related macular degeneration (AMD). Studies have documented not only the effects of white light exposure, but also other wavelengths using LEDs, such as blue or green light. Recently, a blue LED-induced phototoxicity (LIP) model has been developed that causes focal damage in the outer layers of the superior-temporal region of the retina in rodents. In vivo studies described a progressive reduction in retinal thickness that affected the most extensively the photoreceptor layer. Functionally, a transient reduction in a- and b-wave amplitude of the ERG response was observed. Ex vivo studies showed a progressive reduction of cones and an involvement of retinal pigment epithelium cells in the area of the lesion and, in parallel, an activation of microglial cells that perfectly circumscribe the damage in the outer retinal layer. The use of neuroprotective strategies such as intravitreal administration of trophic factors, e.g., basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) or pigment epithelium-derived factor (PEDF) and topical administration of the selective alpha-2 agonist (Brimonidine) have demonstrated to increase the survival of the cone population after LIP.
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Affiliation(s)
- Juan A. Miralles de Imperial-Ollero
- Departamento de Oftalmología, Universidad de Murcia e Instituto Murciano de Investigación Biosanitaria (IMIB) Virgen de la Arrixaca, Campus de CC de la Salud, El Palmar, 30120 Murcia, Spain; (J.A.M.d.I.-O.); (A.G.-O.); (M.P.V.-P.)
| | - Alejandro Gallego-Ortega
- Departamento de Oftalmología, Universidad de Murcia e Instituto Murciano de Investigación Biosanitaria (IMIB) Virgen de la Arrixaca, Campus de CC de la Salud, El Palmar, 30120 Murcia, Spain; (J.A.M.d.I.-O.); (A.G.-O.); (M.P.V.-P.)
| | - Arturo Ortín-Martínez
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON M5T 2S8, Canada;
| | - María Paz Villegas-Pérez
- Departamento de Oftalmología, Universidad de Murcia e Instituto Murciano de Investigación Biosanitaria (IMIB) Virgen de la Arrixaca, Campus de CC de la Salud, El Palmar, 30120 Murcia, Spain; (J.A.M.d.I.-O.); (A.G.-O.); (M.P.V.-P.)
| | - Francisco J. Valiente-Soriano
- Departamento de Oftalmología, Universidad de Murcia e Instituto Murciano de Investigación Biosanitaria (IMIB) Virgen de la Arrixaca, Campus de CC de la Salud, El Palmar, 30120 Murcia, Spain; (J.A.M.d.I.-O.); (A.G.-O.); (M.P.V.-P.)
- Correspondence: (F.J.V.-S.); (M.V.-S.); Tel.: +34-868-88-4503 (F.J.V-S.); +34-868-88-4330 (M.V.-S.)
| | - Manuel Vidal-Sanz
- Departamento de Oftalmología, Universidad de Murcia e Instituto Murciano de Investigación Biosanitaria (IMIB) Virgen de la Arrixaca, Campus de CC de la Salud, El Palmar, 30120 Murcia, Spain; (J.A.M.d.I.-O.); (A.G.-O.); (M.P.V.-P.)
- Correspondence: (F.J.V.-S.); (M.V.-S.); Tel.: +34-868-88-4503 (F.J.V-S.); +34-868-88-4330 (M.V.-S.)
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Abstract
Light has a crucial role in the visual process. For nonvisible radiation in the short-wave spectrum, there are natural mechanisms that protect the human retina from damaging ultraviolet (UV) radiation. Here, the dose (= energy) makes the poison. Damage caused by UV light mainly affects the outer retina, particularly the photoreceptors and the retinal pigment epithelium. While retinal damage due to increased UV radiation exposure can potentially still occur up to the age of 20, in adulthood, exposure of the retina to UV radiation can no longer be assumed, due to decreasing transmission properties of the natural lens. The natural lens, modern intraocular lenses, and wearing of sunglasses with appropriate filter function, particularly in childhood and adolescence, provide a relevant reduction in UV radiation exposure of the retina.
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Affiliation(s)
| | - Thomas Ach
- Augenklinik, Universitätsklinikum Bonn, Venusberg-Campus 1, 53127, Bonn, Deutschland.
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28
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Kiser PD. Retinal pigment epithelium 65 kDa protein (RPE65): An update. Prog Retin Eye Res 2021; 88:101013. [PMID: 34607013 PMCID: PMC8975950 DOI: 10.1016/j.preteyeres.2021.101013] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/21/2021] [Accepted: 09/24/2021] [Indexed: 12/21/2022]
Abstract
Vertebrate vision critically depends on an 11-cis-retinoid renewal system known as the visual cycle. At the heart of this metabolic pathway is an enzyme known as retinal pigment epithelium 65 kDa protein (RPE65), which catalyzes an unusual, possibly biochemically unique, reaction consisting of a coupled all-trans-retinyl ester hydrolysis and alkene geometric isomerization to produce 11-cis-retinol. Early work on this isomerohydrolase demonstrated its membership to the carotenoid cleavage dioxygenase superfamily and its essentiality for 11-cis-retinal production in the vertebrate retina. Three independent studies published in 2005 established RPE65 as the actual isomerohydrolase instead of a retinoid-binding protein as previously believed. Since the last devoted review of RPE65 enzymology appeared in this journal, major advances have been made in a number of areas including our understanding of the mechanistic details of RPE65 isomerohydrolase activity, its phylogenetic origins, the relationship of its membrane binding affinity to its catalytic activity, its role in visual chromophore production for rods and cones, its modulation by macromolecules and small molecules, and the involvement of RPE65 mutations in the development of retinal diseases. In this article, I will review these areas of progress with the goal of integrating results from the varied experimental approaches to provide a comprehensive picture of RPE65 biochemistry. Key outstanding questions that may prove to be fruitful future research pursuits will also be highlighted.
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Affiliation(s)
- Philip D Kiser
- Research Service, VA Long Beach Healthcare System, Long Beach, CA, 90822, USA; Department of Physiology & Biophysics, University of California, Irvine School of Medicine, Irvine, CA, 92697, USA; Department of Ophthalmology and Center for Translational Vision Research, Gavin Herbert Eye Institute, University of California, Irvine School of Medicine, Irvine, CA, 92697, USA.
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29
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Ohishi K, Hosono K, Obana A, Noda A, Hiramitsu T, Hotta Y, Minoshima S. Identification of susceptibility loci for light-induced visual impairment in rats. Exp Eye Res 2021; 210:108688. [PMID: 34237304 DOI: 10.1016/j.exer.2021.108688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 06/14/2021] [Accepted: 06/29/2021] [Indexed: 12/01/2022]
Abstract
Bright light exposure in animals results in the selective degeneration of the outer retina, known as "retinal photic injury" (RPI). The susceptibility to RPI differs among rat strains. WKY rats display susceptibility to RPI with extensive retinal degeneration observed in the sagittal eye specimen, whereas LEW strain rats are resistant to it, showing only slight or no degeneration. In the present study, we first established an ethological screening method using the Morris water maze to discern differential susceptibility among the living rats. WKY and LEW were crossed to produce the first filial generation (F1) offspring. Maze-trained individuals were exposed to bright, white light. The screening test results demonstrated that the susceptibility to light-induced visual impairment in rats is a dominant Mendelian susceptibility trait, as F1 rats were susceptible to visual impairment like WKY rats. Therefore, F1 rats were backcrossed with recessive LEW to produce the first backcross offspring (BC1). Subsequent recurrent backcrossing while selecting for the susceptibility, indicated a segregation ratio of ca. 24% in BC1 and BC2 generations, indicating the involvement of two or more genes in the susceptibility. Further, microsatellite analysis of BC1-to-BC4 individuals using microsatellite markers mapped two susceptibility loci on chromosome segments 5q36 and 19q11-q12, named RPI susceptibility (Rpi)1 and Rpi2, respectively. This study provides an insight into mechanisms underlying differential susceptibility, which could help decipher the mechanism underlying the onset/progression of human age-related macular degeneration.
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Affiliation(s)
- Kentaro Ohishi
- Department of Photomedical Genomics, Institute for Medical Photonics Research, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
| | - Katsuhiro Hosono
- Department of Ophthalmology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Akira Obana
- Hamamatsu BioPhotonics Innovation Chair, Institute for Medical Photonics Research, Preeminent Medical Photonics Education and Research Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan; Department of Ophthalmology, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Naka-ku, Hamamatsu, 430-8558, Japan
| | - Akio Noda
- Department of Integrated Human Sciences (Mathematics), Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Tadahisa Hiramitsu
- Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Yoshihiro Hotta
- Department of Ophthalmology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Shinsei Minoshima
- Department of Photomedical Genomics, Institute for Medical Photonics Research, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
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Phototoxicities Caused by Continuous Light Exposure Were Not Induced in Retinal Ganglion Cells Transduced by an Optogenetic Gene. Int J Mol Sci 2021; 22:ijms22136732. [PMID: 34201658 PMCID: PMC8269149 DOI: 10.3390/ijms22136732] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/16/2021] [Accepted: 06/22/2021] [Indexed: 11/16/2022] Open
Abstract
The death of photoreceptor cells is induced by continuous light exposure. However, it is unclear whether light damage was induced in retinal ganglion cells with photosensitivity by transduction of optogenetic genes. In this study, we evaluated the phototoxicities of continuous light exposure on retinal ganglion cells after transduction of the optogenetic gene mVChR1 using an adeno-associated virus vector. Rats were exposed to continuous light for a week, and visually evoked potentials (VEPs) were recorded. The intensities of continuous light (500, 1000, 3000, and 5000 lx) increased substantially after VEP recordings. After the final recording of VEPs, retinal ganglion cells (RGCs) were retrogradely labeled with a fluorescein tracer, FluoroGold, and the number of retinal ganglion cells was counted under a fluorescent microscope. There was no significant reduction in the amplitudes of VEPs and the number of RGCs after exposure to any light intensity. These results indicated that RGCs were photosensitive after the transduction of optogenetic genes and did not induce any phototoxicity by continuous light exposure.
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31
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Butler JM, Supharattanasitthi W, Yang YC, Paraoan L. RNA-seq analysis of ageing human retinal pigment epithelium: Unexpected up-regulation of visual cycle gene transcription. J Cell Mol Med 2021; 25:5572-5585. [PMID: 33934486 PMCID: PMC8184696 DOI: 10.1111/jcmm.16569] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/07/2021] [Accepted: 04/09/2021] [Indexed: 02/06/2023] Open
Abstract
Ageing presents adverse effects on the retina and is the primary risk factor for age‐related macular degeneration (AMD). We report the first RNA‐seq analysis of age‐related transcriptional changes in the human retinal pigment epithelium (RPE), the primary site of AMD pathogenesis. Whole transcriptome sequencing of RPE from human donors ranging in age from 31 to 93 reveals that ageing is associated with increasing transcription of main RPE‐associated visual cycle genes (including LRAT, RPE65, RDH5, RDH10, RDH11; pathway enrichment BH‐adjusted P = 4.6 × 10−6). This positive correlation is replicated in an independent set of 28 donors and a microarray dataset of 50 donors previously published. LRAT expression is positively regulated by retinoid by‐products of the visual cycle (A2E and all‐trans‐retinal) involving modulation by retinoic acid receptor alpha transcription factor. The results substantiate a novel age‐related positive feedback mechanism between accumulation of retinoid by‐products in the RPE and the up‐regulation of visual cycle genes.
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Affiliation(s)
- Joe M Butler
- Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Wasu Supharattanasitthi
- Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Yit C Yang
- Department of Ophthalmology, Wolverhampton Eye Infirmary, New Cross Hospital, Wolverhampton, UK
| | - Luminita Paraoan
- Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
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32
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Nam S, Kim YK, Kim K, Hong HS, Yu SY, Kim ES. Effects of Blue Light on Eye of Zebra Fish and Protective Role of Polyphenolic Compounds. JOURNAL OF THE KOREAN OPHTHALMOLOGICAL SOCIETY 2021. [DOI: 10.3341/jkos.2021.62.1.77] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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33
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Kiser PD, Palczewski K. Pathways and disease-causing alterations in visual chromophore production for vertebrate vision. J Biol Chem 2021; 296:100072. [PMID: 33187985 PMCID: PMC7948990 DOI: 10.1074/jbc.rev120.014405] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/12/2020] [Accepted: 11/13/2020] [Indexed: 12/14/2022] Open
Abstract
All that we view of the world begins with an ultrafast cis to trans photoisomerization of the retinylidene chromophore associated with the visual pigments of rod and cone photoreceptors. The continual responsiveness of these photoreceptors is then sustained by regeneration processes that convert the trans-retinoid back to an 11-cis configuration. Recent biochemical and electrophysiological analyses of the retinal G-protein-coupled receptor (RGR) suggest that it could sustain the responsiveness of photoreceptor cells, particularly cones, even under bright light conditions. Thus, two mechanisms have evolved to accomplish the reisomerization: one involving the well-studied retinoid isomerase (RPE65) and a second photoisomerase reaction mediated by the RGR. Impairments to the pathways that transform all-trans-retinal back to 11-cis-retinal are associated with mild to severe forms of retinal dystrophy. Moreover, with age there also is a decline in the rate of chromophore regeneration. Both pharmacological and genetic approaches are being used to bypass visual cycle defects and consequently mitigate blinding diseases. Rapid progress in the use of genome editing also is paving the way for the treatment of disparate retinal diseases. In this review, we provide an update on visual cycle biochemistry and then discuss visual-cycle-related diseases and emerging therapeutics for these disorders. There is hope that these advances will be helpful in treating more complex diseases of the eye, including age-related macular degeneration (AMD).
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Affiliation(s)
- Philip D Kiser
- The Department of Physiology & Biophysics, University of California, Irvine, California, USA; Research Service, The VA Long Beach Health Care System, Long Beach, California, USA; The Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, California, USA.
| | - Krzysztof Palczewski
- The Department of Physiology & Biophysics, University of California, Irvine, California, USA; The Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, California, USA; The Department of Chemistry, University of California, Irvine, California, USA.
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34
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Sabry DA, El-Badry D. Altered retina and cornea of Clarias gariepinus (Siluriformes: Clariidae) under the effect of bright and dim lights. ZOOLOGIA 2020. [DOI: 10.3897/zoologia.37.e51603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The purpose of this study was to investigate the influence of constant bright light on the cornea and retina of Clarias gariepinus (Burchell, 1822) and to examine whether it can change after constant exposure to dim light. Twenty-one adult individuals of C. gariepinus were divided into three groups (n = 7). The first group was maintained under normal light (NL). The second group was exposed to the intense bright light (BL) (3020 Lux) of white light lamps for seven days. The third group was exposed to dim light for seven days (DL) following the previous exposure to intense bright light for seven days. The eyes of each fish group were removed and fixed. The following aspects of the eye were investigated: histopathological, immunohistochemical (GFAP and BAX) staining and biochemical study for lactic dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA) and glucose-6-phosphate-dehydrogenase (G6PDH). Also, isoenzyme electrophoresis of LDH, G6PDH and SOD were performed. The present study found that, seven-days BL exposure caused damage to both cornea and retina. However, after exposure to dim-light after bright light there was partial improvement in corneal and retinal structure and an increase in the assayed SOD and G6PDH levels, along with a reduction in MDA content and activity of LDH. These findings demonstrate a plasticity that may help C. gariepinus survive disturbances in the aquatic environment.
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35
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Hernández-Rodríguez EW, Escorcia AM, van der Kamp MW, Montero-Alejo AL, Caballero J. Multi-scale simulation reveals that an amino acid substitution increases photosensitizing reaction inputs in Rhodopsins. J Comput Chem 2020; 41:2278-2295. [PMID: 32757375 DOI: 10.1002/jcc.26392] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 06/27/2020] [Accepted: 07/04/2020] [Indexed: 11/11/2022]
Abstract
Evaluating the availability of molecular oxygen (O2 ) and energy of excited states in the retinal binding site of rhodopsin is a crucial challenging first step to understand photosensitizing reactions in wild-type (WT) and mutant rhodopsins by absorbing visible light. In the present work, energies of the ground and excited states related to 11-cis-retinal and the O2 accessibility to the β-ionone ring are evaluated inside WT and human M207R mutant rhodopsins. Putative O2 pathways within rhodopsins are identified by using molecular dynamics simulations, Voronoi-diagram analysis, and implicit ligand sampling while retinal energetic properties are investigated through density functional theory, and quantum mechanical/molecular mechanical methods. Here, the predictions reveal that an amino acid substitution can lead to enough energy and O2 accessibility in the core hosting retinal of mutant rhodopsins to favor the photosensitized singlet oxygen generation, which can be useful in understanding retinal degeneration mechanisms and in designing blue-lighting-absorbing proteic photosensitizers.
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Affiliation(s)
- Erix W Hernández-Rodríguez
- Laboratorio de Bioinformática y Química Computacional, Escuela de Química y Farmacia, Facultad de Medicina, Universidad Católica del Maule, Talca, Chile
| | - Andrés M Escorcia
- School of Biochemistry, University of Bristol, University Walk, Bristol, UK
| | | | - Ana L Montero-Alejo
- Departamento de Física, Facultad de Ciencias Naturales, Matemática y del Medio Ambiente (FCNMM), Universidad Tecnológica Metropolitana, Santiago, Chile
| | - Julio Caballero
- Departamento de Bioinformática, Centro de Bioinformática, Simulación y Modelado (CBSM), Facultad de Ingeniería, Universidad de Talca, Talca, Chile
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36
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Phototoxic damage to cone photoreceptors can be independent of the visual pigment: the porphyrin hypothesis. Cell Death Dis 2020; 11:711. [PMID: 32862199 PMCID: PMC7456424 DOI: 10.1038/s41419-020-02918-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 08/01/2020] [Accepted: 08/03/2020] [Indexed: 01/20/2023]
Abstract
Lighting is rapidly changing with the introduction of light-emitting diodes (LEDs) in our homes, workplaces, and cities. This evolution of our optical landscape raises major concerns regarding phototoxicity to the retina since light exposure is an identified risk factor for the development of age-related macular degeneration (AMD). In this disease, cone photoreceptors degenerate while the retinal pigment epithelium (RPE) is accumulating lipofuscin containing phototoxic compounds such as A2E. Therefore, it remains unclear if the light-elicited degenerative process is initiated in cones or in the RPE. Using purified cone photoreceptors from pig retina, we here investigated the effect of light on cone survival from 390 to 510 nm in 10 nm steps, plus the 630 nm band. If at a given intensity (0.2 mW/cm²), the most toxic wavelengths are comprised in the visible-to-near-UV range, they shift to blue-violet light (425–445 nm) when exposing cells to a solar source filtered by the eye optics. In contrast to previous rodent studies, this cone photoreceptor phototoxicity is not related to light absorption by the visual pigment. Despite bright flavin autofluorescence of cone inner segment, excitation–emission matrix of this inner segment suggested that cone phototoxicity was instead caused by porphyrin. Toxic light intensities were lower than those previously defined for A2E-loaded RPE cells indicating cones are the first cells at risk for a direct light insult. These results are essential to normative regulations of new lighting but also for the prevention of human retinal pathologies since toxic solar light intensities are encountered even at high latitudes.
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37
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Taveau N, Cubizolle A, Guillou L, Pinquier N, Moine E, Cia D, Kalatzis V, Vercauteren J, Durand T, Crauste C, Brabet P. Preclinical pharmacology of a lipophenol in a mouse model of light-induced retinopathy. Exp Mol Med 2020; 52:1090-1101. [PMID: 32641711 PMCID: PMC8080701 DOI: 10.1038/s12276-020-0460-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/18/2020] [Accepted: 04/21/2020] [Indexed: 12/17/2022] Open
Abstract
Environmental light has deleterious effects on the outer retina in human retinopathies, such as ABCA4-related Stargardt’s disease and dry age-related macular degeneration. These effects involve carbonyl and oxidative stress, which contribute to retinal cell death and vision loss. Here, we used an albino Abca4−/− mouse model, the outer retina of which shows susceptibility to acute photodamage, to test the protective efficacy of a new polyunsaturated fatty acid lipophenol derivative. Anatomical and functional analyses demonstrated that a single intravenous injection of isopropyl-phloroglucinol-DHA, termed IP-DHA, dose-dependently decreased light-induced photoreceptor degeneration and preserved visual sensitivity. This protective effect persisted for 3 months. IP-DHA did not affect the kinetics of the visual cycle in vivo or the activity of the RPE65 isomerase in vitro. Moreover, IP-DHA administered by oral gavage showed significant protection of photoreceptors against acute light damage. In conclusion, short-term tests in Abca4-deficient mice, following single-dose administration and light exposure, identify IP-DHA as a therapeutic agent for the prevention of retinal degeneration. Treating retinal damage in both aging and young patients might now be easier, thanks to treatment with a lipophenol, an omega-3 fatty acid linked to an antioxidant. The retina is the part of the eye that senses light, aided by light-sensitive pigments. However, these light-sensitive pigments can be converted by light to toxic byproducts, and in some individuals, these toxic byproducts can accumulate, damaging the retina and leading to vision loss. Philippe Brabet at the Montpellier Institute of Neuroscience in France and co-workers found that lipophenol treatment protected retinal cells from damage in a mouse model of retinal disease, and that a single dose has been effective in preserving vision. These results may help in finding new treatments for retinal diseases such as Stargardt disease and age-related macular degeneration.
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Affiliation(s)
- Nicolas Taveau
- Institut des Neurosciences de Montpellier, INSERM U1051, F-34091, Montpellier, France.,Université de Montpellier, F-34091, Montpellier, France
| | - Aurélie Cubizolle
- Institut des Neurosciences de Montpellier, INSERM U1051, F-34091, Montpellier, France.,Université de Montpellier, F-34091, Montpellier, France
| | - Laurent Guillou
- Institut des Neurosciences de Montpellier, INSERM U1051, F-34091, Montpellier, France.,Université de Montpellier, F-34091, Montpellier, France
| | - Nicolas Pinquier
- Institut des Neurosciences de Montpellier, INSERM U1051, F-34091, Montpellier, France
| | - Espérance Moine
- Institut des Biomolecules Max Mousseron (IBMM), UMR 5247 - Université de Montpellier, CNRS, ENSCM, F-34095, Montpellier, France
| | - David Cia
- Laboratoire de Biophysique Neurosensorielle, UMR INSERM 1107, Facultés de Médecine et de Pharmacie, F-63001, Clermont-Ferrand, France
| | - Vasiliki Kalatzis
- Institut des Neurosciences de Montpellier, INSERM U1051, F-34091, Montpellier, France.,Université de Montpellier, F-34091, Montpellier, France
| | - Joseph Vercauteren
- Institut des Biomolecules Max Mousseron (IBMM), UMR 5247 - Université de Montpellier, CNRS, ENSCM, F-34095, Montpellier, France
| | - Thierry Durand
- Institut des Biomolecules Max Mousseron (IBMM), UMR 5247 - Université de Montpellier, CNRS, ENSCM, F-34095, Montpellier, France
| | - Céline Crauste
- Institut des Biomolecules Max Mousseron (IBMM), UMR 5247 - Université de Montpellier, CNRS, ENSCM, F-34095, Montpellier, France
| | - Philippe Brabet
- Institut des Neurosciences de Montpellier, INSERM U1051, F-34091, Montpellier, France. .,Université de Montpellier, F-34091, Montpellier, France.
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38
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Tisi A, Flati V, Delle Monache S, Lozzi L, Passacantando M, Maccarone R. Nanoceria Particles Are an Eligible Candidate to Prevent Age-Related Macular Degeneration by Inhibiting Retinal Pigment Epithelium Cell Death and Autophagy Alterations. Cells 2020; 9:cells9071617. [PMID: 32635502 PMCID: PMC7408137 DOI: 10.3390/cells9071617] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 06/30/2020] [Accepted: 07/02/2020] [Indexed: 12/17/2022] Open
Abstract
Retinal pigment epithelium (RPE) dysfunction and degeneration underlie the development of age-related macular degeneration (AMD), which is the leading cause of blindness worldwide. In this study, we investigated whether cerium oxide nanoparticles (CeO2-NPs or nanoceria), which are anti-oxidant agents with auto-regenerative properties, are able to preserve the RPE. On ARPE-19 cells, we found that CeO2-NPs promoted cell viability against H2O2-induced cellular damage. For the in vivo studies, we used a rat model of acute light damage (LD), which mimics many features of AMD. CeO2-NPs intravitreally injected three days before LD prevented RPE cell death and degeneration and nanoceria labelled with fluorescein were found localized in the cytoplasm of RPE cells. CeO2-NPs inhibited epithelial-mesenchymal transition of RPE cells and modulated autophagy by the down-regulation of LC3B-II and p62. Moreover, the treatment inhibited nuclear localization of LC3B. Taken together, our study demonstrates that CeO2-NPs represent an eligible candidate to counteract RPE degeneration and, therefore, a powerful therapy for AMD.
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Affiliation(s)
- Annamaria Tisi
- Department of Biotechnology and Applied Clinical Sciences, University of L’Aquila, via Vetoio, Coppito 2, 67100 L’Aquila, Italy; (A.T.); (V.F.); (S.D.M.)
| | - Vincenzo Flati
- Department of Biotechnology and Applied Clinical Sciences, University of L’Aquila, via Vetoio, Coppito 2, 67100 L’Aquila, Italy; (A.T.); (V.F.); (S.D.M.)
| | - Simona Delle Monache
- Department of Biotechnology and Applied Clinical Sciences, University of L’Aquila, via Vetoio, Coppito 2, 67100 L’Aquila, Italy; (A.T.); (V.F.); (S.D.M.)
| | - Luca Lozzi
- Department of Physical and Chemical Sciences, University of L’Aquila, via Vetoio, Coppito 1, 67100 L’Aquila, Italy; (L.L.); (M.P.)
| | - Maurizio Passacantando
- Department of Physical and Chemical Sciences, University of L’Aquila, via Vetoio, Coppito 1, 67100 L’Aquila, Italy; (L.L.); (M.P.)
| | - Rita Maccarone
- Department of Biotechnology and Applied Clinical Sciences, University of L’Aquila, via Vetoio, Coppito 2, 67100 L’Aquila, Italy; (A.T.); (V.F.); (S.D.M.)
- Correspondence: ; Tel.: +39-0862433488
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Saccà SC, Vernazza S, Iorio EL, Tirendi S, Bassi AM, Gandolfi S, Izzotti A. Molecular changes in glaucomatous trabecular meshwork. Correlations with retinal ganglion cell death and novel strategies for neuroprotection. PROGRESS IN BRAIN RESEARCH 2020; 256:151-188. [PMID: 32958211 DOI: 10.1016/bs.pbr.2020.06.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Glaucoma is a chronic neurodegenerative disease characterized by retinal ganglion cell loss. Although significant advances in ophthalmologic knowledge and practice have been made, some glaucoma mechanisms are not yet understood, therefore, up to now there is no effective treatment able to ensure healing. Indeed, either pharmacological or surgical approaches to this disease aim in lowering intraocular pressure, which is considered the only modifiable risk factor. However, it is well known that several factors and metabolites are equally (if not more) involved in glaucoma. Oxidative stress, for instance, plays a pivotal role in both glaucoma onset and progression because it is responsible for the trabecular meshwork cell damage and, consequently, for intraocular pressure increase as well as for glaucomatous damage cascade. This review at first shows accurately the molecular-derived dysfunctions in antioxidant system and in mitochondria homeostasis which due to both oxidative stress and aging, lead to a chronic inflammation state, the trabecular meshwork damage as well as the glaucoma neurodegeneration. Therefore, the main molecular events triggered by oxidative stress up to the proapoptotic signals that promote the ganglion cell death have been highlighted. The second part of this review, instead, describes some of neuroprotective agents such as polyphenols or polyunsaturated fatty acids as possible therapeutic source against the propagation of glaucomatous damage.
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Affiliation(s)
- Sergio C Saccà
- Policlinico San Martino University Hospital, Department of Neuroscience and sense organs, Ophthalmology Unit, Genoa, Italy.
| | | | | | - Sara Tirendi
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy; Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), Pisa, Italy
| | - Anna Maria Bassi
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy; Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), Pisa, Italy
| | - Stefano Gandolfi
- Ophthalmology Unit, Department of Biological, Biotechnological and Translational Sciences, University of Parma, Parma, Italy
| | - Alberto Izzotti
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy; Mutagenesis Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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40
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Sundar JC, Munezero D, Bryan-Haring C, Saravanan T, Jacques A, Ramamurthy V. Rhodopsin signaling mediates light-induced photoreceptor cell death in rd10 mice through a transducin-independent mechanism. Hum Mol Genet 2020; 29:394-406. [PMID: 31925423 PMCID: PMC7015845 DOI: 10.1093/hmg/ddz299] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 11/22/2019] [Accepted: 12/02/2019] [Indexed: 01/08/2023] Open
Abstract
Retinitis pigmentosa (RP) is a debilitating blinding disease affecting over 1.5 million people worldwide, but the mechanisms underlying this disease are not well understood. One of the common models used to study RP is the retinal degeneration-10 (rd10) mouse, which has a mutation in Phosphodiesterase-6b (Pde6b) that causes a phenotype mimicking the human disease. In rd10 mice, photoreceptor cell death occurs with exposure to normal light conditions, but as demonstrated in this study, rearing these mice in dark preserves their retinal function. We found that inactivating rhodopsin signaling protected photoreceptors from degeneration suggesting that the pathway activated by this G-protein-coupled receptor is causing light-induced photoreceptor cell death in rd10 mice. However, inhibition of transducin signaling did not prevent the loss of photoreceptors in rd10 mice reared under normal light conditions implying that the degeneration caused by rhodopsin signaling is not mediated through its canonical G-protein transducin. Inexplicably, loss of transducin in rd10 mice also led to photoreceptor cell death in darkness. Furthermore, we found that the rd10 mutation in Pde6b led to a reduction in the assembled PDE6αβγ2 complex, which was corroborated by our data showing mislocalization of the γ subunit. Based on our findings and previous studies, we propose a model where light activates a non-canonical pathway mediated by rhodopsin but independent of transducin that sensitizes cyclic nucleotide gated channels to cGMP and causes photoreceptor cell death. These results generate exciting possibilities for treatment of RP patients without affecting their vision or the canonical phototransduction cascade.
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Affiliation(s)
- Jesse C Sundar
- Departments of Biochemistry, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26505, USA
| | - Daniella Munezero
- Departments of Ophthalmology and Visual Sciences, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26505, USA
| | - Caitlyn Bryan-Haring
- Departments of Biochemistry, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26505, USA
| | - Thamaraiselvi Saravanan
- Departments of Ophthalmology and Visual Sciences, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26505, USA
| | - Angelica Jacques
- Departments of Ophthalmology and Visual Sciences, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26505, USA
| | - Visvanathan Ramamurthy
- Departments of Biochemistry, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26505, USA
- Departments of Ophthalmology and Visual Sciences, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26505, USA
- Departments of Neuroscience, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26505, USA
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Chaya T, Tsutsumi R, Varner LR, Maeda Y, Yoshida S, Furukawa T. Cul3-Klhl18 ubiquitin ligase modulates rod transducin translocation during light-dark adaptation. EMBO J 2019; 38:e101409. [PMID: 31696965 DOI: 10.15252/embj.2018101409] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 09/30/2019] [Accepted: 10/08/2019] [Indexed: 01/02/2023] Open
Abstract
Adaptation is a general feature of sensory systems. In rod photoreceptors, light-dependent transducin translocation and Ca2+ homeostasis are involved in light/dark adaptation and prevention of cell damage by light. However, the underlying regulatory mechanisms remain unclear. Here, we identify mammalian Cul3-Klhl18 ubiquitin ligase as a transducin translocation modulator during light/dark adaptation. Under dark conditions, Klhl18-/- mice exhibited decreased rod light responses and subcellular localization of the transducin α-subunit (Tα), similar to that observed in light-adapted Klhl18+/+ mice. Cul3-Klhl18 promoted ubiquitination and degradation of Unc119, a rod Tα-interacting protein. Unc119 overexpression phenocopied Tα mislocalization observed in Klhl18-/- mice. Klhl18 weakly recognized casein kinase-2-phosphorylated Unc119 protein, which is dephosphorylated by Ca2+ -dependent phosphatase calcineurin. Calcineurin inhibition increased Unc119 expression and Tα mislocalization in rods. These results suggest that Cul3-Klhl18 modulates rod Tα translocation during light/dark adaptation through Unc119 ubiquitination, which is affected by phosphorylation. Notably, inactivation of the Cul3-Klhl18 ligase and calcineurin inhibitors FK506 and cyclosporine A that are known immunosuppressant drugs repressed light-induced photoreceptor damage, suggesting potential therapeutic targets.
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Affiliation(s)
- Taro Chaya
- Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, Osaka, Japan
| | - Ryotaro Tsutsumi
- Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, Osaka, Japan
| | - Leah Rie Varner
- Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, Osaka, Japan
| | - Yamato Maeda
- Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, Osaka, Japan
| | - Satoyo Yoshida
- Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, Osaka, Japan
| | - Takahisa Furukawa
- Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, Osaka, Japan
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42
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Zhang J, Choi EH, Tworak A, Salom D, Leinonen H, Sander CL, Hoang TV, Handa JT, Blackshaw S, Palczewska G, Kiser PD, Palczewski K. Photic generation of 11- cis-retinal in bovine retinal pigment epithelium. J Biol Chem 2019; 294:19137-19154. [PMID: 31694912 DOI: 10.1074/jbc.ra119.011169] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 10/25/2019] [Indexed: 12/19/2022] Open
Abstract
Photoisomerization of the 11-cis-retinal chromophore of rod and cone visual pigments to an all-trans-configuration is the initiating event for vision in vertebrates. The regeneration of 11-cis-retinal, necessary for sustained visual function, is an endergonic process normally conducted by specialized enzyme systems. However, 11-cis-retinal also can be formed through reverse photoisomerization from all-trans-retinal. A nonvisual opsin known as retinal pigment epithelium (RPE)-retinal G-protein-coupled receptor (RGR) was previously shown to mediate visual chromophore regeneration in photic conditions, but conflicting results have cast doubt on its role as a photoisomerase. Here, we describe high-level production of 11-cis-retinal from RPE membranes stimulated by illumination at a narrow band of wavelengths. This activity was associated with RGR and enhanced by cellular retinaldehyde-binding protein (CRALBP), which binds the 11-cis-retinal produced by RGR and prevents its re-isomerization to all-trans-retinal. The activity was recapitulated with cells heterologously expressing RGR and with purified recombinant RGR. Using an RGR variant, K255A, we confirmed that a Schiff base linkage at Lys-255 is critical for substrate binding and isomerization. Single-cell RNA-Seq analysis of the retina and RPE tissue confirmed that RGR is expressed in human and bovine RPE and Müller glia, whereas mouse RGR is expressed in RPE but not in Müller glia. These results provide key insights into the mechanisms of physiological retinoid photoisomerization and suggest a novel mechanism by which RGR, in concert with CRALBP, regenerates the visual chromophore in the RPE under sustained light conditions.
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Affiliation(s)
- Jianye Zhang
- Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, California 92697
| | - Elliot H Choi
- Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, California 92697.,Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106
| | - Aleksander Tworak
- Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, California 92697
| | - David Salom
- Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, California 92697
| | - Henri Leinonen
- Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, California 92697
| | - Christopher L Sander
- Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, California 92697.,Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106
| | - Thanh V Hoang
- Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - James T Handa
- Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287
| | - Seth Blackshaw
- Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.,Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287
| | | | - Philip D Kiser
- Department of Physiology and Biophysics, University of California, Irvine, California 92697.,Research Service, Veterans Affairs Long Beach Healthcare System, Long Beach, California 90822
| | - Krzysztof Palczewski
- Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, California 92697
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43
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Li S, Green JF, Jin M. Impacts of deletion and ichthyosis prematurity syndrome-associated mutations in fatty acid transport protein 4 on the function of RPE65. FEBS Lett 2019; 594:540-552. [PMID: 31595490 DOI: 10.1002/1873-3468.13633] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 09/16/2019] [Accepted: 09/16/2019] [Indexed: 12/23/2022]
Abstract
The retinal pigment epithelium-specific 65 kDa (RPE65) isomerase plays a pivotal role in photoreceptor survival and function. RPE65-catalyzed synthesis of 11-cis-retinol from all-trans-retinyl esters in the visual cycle is negatively regulated, through a heretofore unknown mechanism, by the fatty acid transport protein FATP4, mutations in which are associated with ichthyosis prematurity syndrome (IPS). Here, we analyzed the interaction between deletion mutants of FATP4 and RPE65 and the impacts of IPS-associated FATP4 mutations on RPE65 expression, 11-cis-retinol synthesis, and all-trans-retinyl ester synthesis. Our results suggest that the interaction between FATP4 and RPE65 contributes to the inhibition of RPE65 function and that IPS-associated nonsense and missense mutations in FATP4 have different effects on the visual cycle.
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Affiliation(s)
- Songhua Li
- Neuroscience Center of Excellence, Louisiana State University School of Medicine, New Orleans, LA, USA
| | - John F Green
- Neuroscience Center of Excellence, Louisiana State University School of Medicine, New Orleans, LA, USA
| | - Minghao Jin
- Neuroscience Center of Excellence, Louisiana State University School of Medicine, New Orleans, LA, USA.,Department of Ophthalmology, Louisiana State University School of Medicine, New Orleans, LA, USA
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44
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Tao JX, Zhou WC, Zhu XG. Mitochondria as Potential Targets and Initiators of the Blue Light Hazard to the Retina. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:6435364. [PMID: 31531186 PMCID: PMC6721470 DOI: 10.1155/2019/6435364] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 06/18/2019] [Accepted: 07/25/2019] [Indexed: 12/20/2022]
Abstract
Commercially available white light-emitting diodes (LEDs) have an intense emission in the range of blue light, which has raised a range of public concerns about their potential risks as retinal hazards. Distinct from other visible light components, blue light is characterized by short wavelength, high energy, and strong penetration that can reach the retina with relatively little loss in damage potential. Mitochondria are abundant in retinal tissues, giving them relatively high access to blue light, and chromophores, which are enriched in the retina, have many mitochondria able to absorb blue light and induce photochemical effects. Therefore, excessive exposure of the retina to blue light tends to cause ROS accumulation and oxidative stress, which affect the structure and function of the retinal mitochondria and trigger mitochondria-involved death signaling pathways. In this review, we highlight the essential roles of mitochondria in blue light-induced photochemical damage and programmed cell death in the retina, indicate directions for future research and preventive targets in terms of the blue light hazard to the retina, and suggest applying LED devices in a rational way to prevent the blue light hazard.
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Affiliation(s)
- Jin-Xin Tao
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
- Department of Clinical Medicine, The Second Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Wen-Chuan Zhou
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
- Department of Clinical Medicine, The Second Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Xin-Gen Zhu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
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45
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Light stress affects cones and horizontal cells via rhodopsin-mediated mechanisms. Exp Eye Res 2019; 186:107719. [PMID: 31291592 DOI: 10.1016/j.exer.2019.107719] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 07/04/2019] [Accepted: 07/04/2019] [Indexed: 01/20/2023]
Abstract
Retinal degenerations are a major cause of blindness in human patients. The identification of endogenous mechanisms involved in neurodegeneration or neuroprotection helps to understand the response of the retina to stress and provides essential information not only for basic retinal physiology but also for defining molecular targets for neuroprotective strategies. Here we used excessive light exposure as a model system to study mechanisms of photoreceptor degeneration in mice. Using one wild type and four genetically modified mouse strains, we demonstrate that light exposure resulted not only in the degeneration of rods but also in an early but transient repression of several cone-specific genes, in a reversible hyperreflectivity of the outer retina including the outer plexiform layer, and in the loss of horizontal cells. The effects on cones, horizontal cells and the inner retina depended on light absorption by rhodopsin and, at least partially, on leukemia inhibitory factor. This demonstrates the existence of intercellular communication routes that transduce rod stress to other cells, likely to provide support for photoreceptors and increase cell survival in the injured retina.
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46
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Clark AJ, Yang P, Khaderi KR, Moshfeghi AA. Ocular Tolerance of Contemporary Electronic Display Devices. Ophthalmic Surg Lasers Imaging Retina 2019; 49:346-354. [PMID: 29772045 DOI: 10.3928/23258160-20180501-08] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 09/21/2017] [Indexed: 11/20/2022]
Abstract
Electronic displays have become an integral part of life in the developed world since the revolution of mobile computing a decade ago. With the release of multiple consumer-grade virtual reality (VR) and augmented reality (AR) products in the past 2 years utilizing head-mounted displays (HMDs), as well as the development of low-cost, smartphone-based HMDs, the ability to intimately interact with electronic screens is greater than ever. VR/AR HMDs also place the display at much closer ocular proximity than traditional electronic devices while also isolating the user from the ambient environment to create a "closed" system between the user's eyes and the display. Whether the increased interaction with these devices places the user's retina at higher risk of damage is currently unclear. Herein, the authors review the discovery of photochemical damage of the retina from visible light as well as summarize relevant clinical and preclinical data regarding the influence of modern display devices on retinal health. Multiple preclinical studies have been performed with modern light-emitting diode technology demonstrating damage to the retina at modest exposure levels, particularly from blue-light wavelengths. Unfortunately, high-quality in-human studies are lacking, and the small clinical investigations performed to date have failed to keep pace with the rapid evolutions in display technology. Clinical investigations assessing the effect of HMDs on human retinal function are also yet to be performed. From the available data, modern consumer electronic displays do not appear to pose any acute risk to vision with average use; however, future studies with well-defined clinical outcomes and illuminance metrics are needed to better understand the long-term risks of cumulative exposure to electronic displays in general and with "closed" VR/AR HMDs in particular. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:346-354.].
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47
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Owoyele BV, Ayilara OG. Coconut oil protects against light-induced retina degeneration in male Wistar rats. PATHOPHYSIOLOGY 2019; 26:89-95. [DOI: 10.1016/j.pathophys.2018.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 09/25/2018] [Accepted: 10/02/2018] [Indexed: 11/26/2022] Open
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48
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Zernii EY, Nazipova AA, Nemashkalova EL, Kazakov AS, Gancharova OS, Serebryakova MV, Tikhomirova NK, Baksheeva VE, Vladimirov VI, Zinchenko DV, Philippov PP, Senin II, Permyakov SE. Light-Induced Thiol Oxidation of Recoverin Affects Rhodopsin Desensitization. Front Mol Neurosci 2019; 11:474. [PMID: 30666186 PMCID: PMC6330308 DOI: 10.3389/fnmol.2018.00474] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 12/05/2018] [Indexed: 02/03/2023] Open
Abstract
The excessive light illumination of mammalian retina is known to induce oxidative stress and photoreceptor cell death linked to progression of age-related macular degeneration. The photochemical damage of photoreceptors is suggested to occur via two apoptotic pathways that involve either excessive rhodopsin activation or constitutive phototransduction, depending on the light intensity. Both pathways are dramatically activated in the absence of rhodopsin desensitization by GRK1. Previously, we have shown that moderate illumination (halogen lamp, 1,500 lx, 1–5 h) of mammalian eyes provokes disulfide dimerization of recoverin, a calcium-dependent regulator of GRK1. Here, we demonstrate under in vivo conditions that both moderate long-term (metal halide lamp, 2,500 lx, 14 h, rat model) and intense short-term (halogen lamp, 30,000 lx for 3 h, rabbit model) illumination of the mammalian retina are accompanied by accumulation of disulfide dimer of recoverin. Furthermore, in the second case we reveal alternatively oxidized derivatives of the protein, apparently including its monomer with sulfinic group. Histological data indicate that thiol oxidation of recoverin precedes apoptosis of photoreceptors. Both disulfide dimer and oxidized monomer (or oxidation mimicking C39D mutant) of recoverin exhibit lowered α-helical content and thermal stability of their apo-forms, as well as increased Ca2+ affinity. Meanwhile, the oxidized monomer and C39D mutant of recoverin demonstrate impaired ability to bind photoreceptor membranes and regulate GRK1, whereas disulfide dimer exhibits notably improved membrane binding and GRK1 inhibition in absence of Ca2+. The latter effect is expected to slow down rhodopsin desensitization in the light, thereby favoring support of the light-induced oxidative stress, ultimately leading to photoreceptor apoptosis. Overall, the intensity and duration of illumination of the retina affect thiol oxidation of recoverin likely contributing to propagation of the oxidative stress and photoreceptor damage.
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Affiliation(s)
- Evgeni Yu Zernii
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.,Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Aliya A Nazipova
- Institute for Biological Instrumentation of the Russian Academy of Sciences, Pushchino, Russia
| | | | - Alexey S Kazakov
- Institute for Biological Instrumentation of the Russian Academy of Sciences, Pushchino, Russia
| | - Olga S Gancharova
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.,Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Marina V Serebryakova
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
| | - Natalya K Tikhomirova
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
| | - Viktoriia E Baksheeva
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
| | - Vasiliy I Vladimirov
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Pushchino, Russia
| | - Dmitry V Zinchenko
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Pushchino, Russia
| | - Pavel P Philippov
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
| | - Ivan I Senin
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
| | - Sergei E Permyakov
- Institute for Biological Instrumentation of the Russian Academy of Sciences, Pushchino, Russia
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49
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Reactive Oxygen Species-Mediated Damage of Retinal Neurons: Drug Development Targets for Therapies of Chronic Neurodegeneration of the Retina. Int J Mol Sci 2018; 19:ijms19113362. [PMID: 30373222 PMCID: PMC6274960 DOI: 10.3390/ijms19113362] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 10/18/2018] [Accepted: 10/19/2018] [Indexed: 02/06/2023] Open
Abstract
The significance of oxidative stress in the development of chronic neurodegenerative diseases of the retina has become increasingly apparent in recent years. Reactive oxygen species (ROS) are free radicals produced at low levels as a result of normal cellular metabolism that are ultimately metabolized and detoxified by endogenous and exogenous mechanisms. In the presence of oxidative cellular stress, ROS are produced in excess, resulting in cellular injury and death and ultimately leading to tissue and organ dysfunction. Recent studies have investigated the role of excess ROS in the pathogenesis and development of chronic neurodegenerative diseases of the retina including glaucoma, diabetic retinopathy, and age-related macular degeneration. Findings from these studies are promising insofar as they provide clear rationales for innovative treatment and prevention strategies of these prevalent and disabling diseases where currently therapeutic options are limited. Here, we briefly outline recent developments that have contributed to our understanding of the role of ROS in the pathogenesis of chronic neurodegenerative diseases of the retina. We then examine and analyze the peer-reviewed evidence in support of ROS as targets for therapy development in the area of chronic neurodegeneration of the retina.
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50
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Castiglione GM, Chang BS. Functional trade-offs and environmental variation shaped ancient trajectories in the evolution of dim-light vision. eLife 2018; 7:35957. [PMID: 30362942 PMCID: PMC6203435 DOI: 10.7554/elife.35957] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 09/09/2018] [Indexed: 12/11/2022] Open
Abstract
Trade-offs between protein stability and activity can restrict access to evolutionary trajectories, but widespread epistasis may facilitate indirect routes to adaptation. This may be enhanced by natural environmental variation, but in multicellular organisms this process is poorly understood. We investigated a paradoxical trajectory taken during the evolution of tetrapod dim-light vision, where in the rod visual pigment rhodopsin, E122 was fixed 350 million years ago, a residue associated with increased active-state (MII) stability but greatly diminished rod photosensitivity. Here, we demonstrate that high MII stability could have likely evolved without E122, but instead, selection appears to have entrenched E122 in tetrapods via epistatic interactions with nearby coevolving sites. In fishes by contrast, selection may have exploited these epistatic effects to explore alternative trajectories, but via indirect routes with low MII stability. Our results suggest that within tetrapods, E122 and high MII stability cannot be sacrificed-not even for improvements to rod photosensitivity.
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Affiliation(s)
- Gianni M Castiglione
- Department of Cell and Systems Biology, University of Toronto, Toronto, Canada.,Department of Ecology and Evolutionary Biology, University of Toronto, Toronto, Canada
| | - Belinda Sw Chang
- Department of Cell and Systems Biology, University of Toronto, Toronto, Canada.,Department of Ecology and Evolutionary Biology, University of Toronto, Toronto, Canada.,Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Canada
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