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Molecular Mechanisms of Retina Degeneration

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 April 2025) | Viewed by 13180

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Special Issue Editor

Prof. Dr. Hemant Khanna

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Pre-Clinical Ocular Research Volunteer Faculty, UMass Chan Medical School, Worcester, MA 01655, USA
Interests: retina; neurodegenerative eye diseases; retinal degeneration
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Special Issue Information

Dear Colleagues,

Retinal degenerative diseases are the leading cause of blindness worldwide. These diseases are associated with immense clinical and genetic heterogeneity, and their manifestation is often influenced by environmental factors. Extensive studies have been performed in various animal models to understand the mechanisms of retinal diseases. However, it has been difficult to effectively translate the results to the clinic. Therefore, the aim of this Special Issue is to understand how the outcomes of the mechanistic and pre-clinical therapeutic studies using different disease modeling platforms can be unified, or at least stratified based on the species, in order to a clearer understanding of the translatability of the studies to humans. We invite researchers and specialists in the field to submit articles on a wide range of retinal degenerative disease fields, focusing in particular on understanding the disease mechanisms and designing therapeutic modalities in the modeling platform of choice. Preference will be given to those articles that also include a correlation guide of their outcomes to what is known or observed in the clinic.

Prof. Dr. Hemant Khanna
Guest Editor

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Keywords

retina
retinal pigment epithelium
age-related macular degeneration
retinal degeneration

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Published Papers (7 papers)

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Research

15 pages, 3126 KiB

Open AccessArticle

Blue Light-Induced Mitochondrial Oxidative Damage Underlay Retinal Pigment Epithelial Cell Apoptosis

by Mohamed Abdouh, Yunxi Chen, Alicia Goyeneche and Miguel N. Burnier

Int. J. Mol. Sci. 2024, 25(23), 12619; https://doi.org/10.3390/ijms252312619 - 24 Nov 2024

Viewed by 2148

Abstract

Reactive oxygen species (ROS) play a pivotal role in apoptosis. We reported that Blue Light (BL) induced oxidative stress in human retinal pigment epithelial (RPE) cells in vitro and increased drusen deposition and RPE cell apoptosis in human eyes. Here, we investigated the mechanisms underlying BL-induced damage to RPE cells. Cells were exposed to BL with or without the antioxidant N-acetylcysteine. Cells were analyzed for levels of ROS, proliferation, viability, and mitochondria membrane potential (ΔΨ_M) fluctuation. We performed proteomic analyses to search for differentially expressed proteins. ROS levels increased following RPE cell exposure to BL. While ROS production did not affect RPE cell proliferation, it was accompanied by decreased ΔΨ_M and increased cell apoptosis due to the caspase cascade activation in a ROS-dependent manner. Proteomic analyses revealed that BL decreased the levels of ROS detoxifying enzymes in exposed cells. We conclude that BL-induced oxidative stress is cytotoxic to RPE cells. These findings bring new insights into the involvement of BL on RPE cell damage and its role in the progression of age-related macular degeneration. The use of antioxidants is an avenue to block or delay BL-mediated RPE cell apoptosis to counteract the disease progression. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Retina Degeneration)

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13 pages, 3831 KiB

Open AccessArticle

Differential Expression of Mitogen-Activated Protein Kinase Signaling Pathways in the Human Choroid–Retinal Pigment Epithelial Complex Indicates Regional Predisposition to Disease

by Dylan R. Hailey, Debolina Kanjilal and Peter Koulen

Int. J. Mol. Sci. 2024, 25(18), 10105; https://doi.org/10.3390/ijms251810105 - 20 Sep 2024

Viewed by 1038

Abstract

The retina is composed of neuronal layers that include several types of interneurons and photoreceptor cells, and separate underlying retinal pigment epithelium (RPE), Bruch’s membrane, and choroid. Different regions of the human retina include the fovea, macula, and periphery, which have unique physiological functions and anatomical features. These regions are also unique in their protein expression, and corresponding cellular and molecular responses to physiological and pathophysiological stimuli. Skeie and Mahajan analyzed regional protein expression in the human choroid–RPE complex. Mitogen-Activated Protein Kinase (MAPK) signaling pathways have been implicated in responses to stimuli such as oxidative stress and inflammation, which are critical factors in retina diseases including age-related macular degeneration. We, therefore, analyzed the Skeie and Mahajan, 2014, dataset for regional differences in the expression of MAPK-related proteins and discussed the potential implications in retinal diseases presenting with regional signs and symptoms. Regional protein expression data from the Skeie and Mahajan, 2014, study were analyzed for members of signaling networks involving MAPK and MAPK-related proteins, categorized by specific MAPK cascades, such as p38, ERK1/2, and JNK1/2, both upstream or downstream of the respective MAPK and MAPK-related proteins. We were able to identify 207 MAPK and MAPK-related proteins, 187 of which belonging to specific MAPK cascades. A total of 31 of these had been identified in the retina with two proteins, DLG2 and FLG downstream, and the other 29 upstream, of MAPK proteins. Our findings provide evidence for potential molecular substrates of retina region-specific disease manifestation and potential new targets for therapeutics development. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Retina Degeneration)

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14 pages, 2695 KiB

Open AccessArticle

Potential Involvements of Cilia-Centrosomal Genes in Primary Congenital Glaucoma

by Goutham Pyatla, Meha Kabra, Anil K. Mandal, Wei Zhang, Ashish Mishra, Samir Bera, Sonika Rathi, Satish Patnaik, Alice A. Anthony, Ritu Dixit, Seema Banerjee, Konegari Shekhar, Srinivas Marmamula, Inderjeet Kaur, Rohit C. Khanna and Subhabrata Chakrabarti

Int. J. Mol. Sci. 2024, 25(18), 10028; https://doi.org/10.3390/ijms251810028 - 18 Sep 2024

Viewed by 1847

Abstract

Primary congenital glaucoma (PCG) occurs in children due to developmental abnormalities in the trabecular meshwork and anterior chamber angle. Previous studies have implicated rare variants in CYP1B1, LTBP2, and TEK and their interactions with MYOC, FOXC1, and PRSS56 in the genetic complexity and clinical heterogeneity of PCG. Given that some of the gene-encoded proteins are localized in the centrosomes (MYOC) and perform ciliary functions (TEK), we explored the involvement of a core centrosomal protein, CEP164, which is responsible for ocular development and regulation of intraocular pressure. Deep sequencing of CEP164 in a PCG cohort devoid of homozygous mutations in candidate genes (n = 298) and controls (n = 1757) revealed CEP164 rare pathogenic variants in 16 cases (5.36%). Co-occurrences of heterozygous alleles of CEP164 with other genes were seen in four cases (1.34%), and a physical interaction was noted for CEP164 and CYP1B1 in HEK293 cells. Cases of co-harboring alleles of the CEP164 and other genes had a poor prognosis compared with those with a single copy of the CEP164 allele. We also screened INPP5E, which synergistically interacts with CEP164, and observed a lower frequency of pathogenic variants (0.67%). Our data suggest the potential involvements of CEP164 and INPP5E and the yet unexplored cilia-centrosomal functions in PCG pathogenesis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Retina Degeneration)

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13 pages, 2845 KiB

Open AccessArticle

Exploring the Associated Genetic Causes of Diabetic Retinopathy as a Model of Inflammation in Retinal Diseases

by Francesco Cappellani, Carl D. Regillo, Julia A. Haller, Caterina Gagliano and Jose S. Pulido

Int. J. Mol. Sci. 2024, 25(10), 5456; https://doi.org/10.3390/ijms25105456 - 17 May 2024

Cited by 2 | Viewed by 1486

Abstract

To investigate potential biomarkers and biological processes associated with diabetic retinopathy (DR) using transcriptomic and proteomic data. The OmicsPred PheWAS application was interrogated to identify genes and proteins associated with DR and diabetes mellitus (DM) at a false discovery rate (FDR)-adjusted p-value of <0.05 and also <0.005. Gene Ontology PANTHER analysis and STRING database analysis were conducted to explore the biological processes and protein interactions related to the identified biomarkers. The interrogation identified 49 genes and 22 proteins associated with DR and/or DM; these were divided into those uniquely associated with diabetic retinopathy, uniquely associated with diabetes mellitus, and the ones seen in both conditions. The Gene Ontology PANTHER and STRING database analyses highlighted associations of several genes and proteins associated with diabetic retinopathy with adaptive immune response, valyl-TRNA aminoacylation, complement activation, and immune system processes. Our analyses highlight potential transcriptomic and proteomic biomarkers for DR and emphasize the association of known aspects of immune response, the complement system, advanced glycosylation end-product formation, and specific receptor and mitochondrial function with DR pathophysiology. These findings may suggest pathways for future research into novel diagnostic and therapeutic strategies for DR. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Retina Degeneration)

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13 pages, 2073 KiB

Open AccessArticle

Fructosyl Amino Oxidase as a Therapeutic Enzyme in Age-Related Macular Degeneration

by Joris R. Delanghe, Jose Diana Di Mavungu, Koen Beerens, Jonas Himpe, Nezahat Bostan, Marijn M. Speeckaert, Henk Vrielinck, Anne Vral, Caroline Van Den Broeke, Manon Huizing and Elisabeth Van Aken

Int. J. Mol. Sci. 2024, 25(9), 4779; https://doi.org/10.3390/ijms25094779 - 27 Apr 2024

Viewed by 1765

Abstract

Age-related macular degeneration (AMD) is an age-related disorder that is a global public health problem. The non-enzymatic Maillard reaction results in the formation of advanced glycation end products (AGEs). Accumulation of AGEs in drusen plays a key role in AMD. AGE-reducing drugs may contribute to the prevention and treatment of AGE-related disease. Fructosamine oxidase (FAOD) acts on fructosyl lysine and fructosyl valine. Based upon the published results of fructosamine 3-kinase (FN3K) and FAOD obtained in cataract and presbyopia, we studied ex vivo FAOD treatment as a non-invasive AMD therapy. On glycolaldehyde-treated porcine retinas, FAOD significantly reduced AGE autofluorescence (p = 0.001). FAOD treatment results in a breakdown of AGEs, as evidenced using UV fluorescence, near-infrared microspectroscopy on stained tissue sections of human retina, and gel permeation chromatography. Drusen are accumulations of AGEs that build up between Bruch’s membrane and the retinal pigment epithelium. On microscopy slides of human retina affected by AMD, a significant reduction in drusen surface to 45 ± 21% was observed following FAOD treatment. Enzymatic digestion followed by mass spectrometry of fructose- and glucose-based AGEs (produced in vitro) revealed a broader spectrum of substrates for FAOD, as compared to FN3K, including the following: fructosyllysine, carboxymethyllysine, carboxyethyllysine, and imidazolone. In contrast to FN3K digestion, agmatine (4-aminobutyl-guanidine) was formed following FAOD treatment in vitro. The present study highlights the therapeutic potential of FAOD in AMD by repairing glycation-induced damage. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Retina Degeneration)

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13 pages, 9343 KiB

Open AccessArticle

Development of TRIB3-Based Therapy as a Gene-Independent Approach to Treat Retinal Degenerative Disorders

by Trong Thuan Ung, Christopher R. Starr, Assylbek Zhylkibayev, Irina Saltykova and Marina Gorbatyuk

Int. J. Mol. Sci. 2024, 25(9), 4716; https://doi.org/10.3390/ijms25094716 - 26 Apr 2024

Cited by 1 | Viewed by 1452

Abstract

Inherited retinal degeneration (RD) constitutes a heterogeneous group of genetic retinal degenerative disorders. The molecular mechanisms underlying RD encompass a diverse spectrum of cellular signaling, with the unfolded protein response (UPR) identified as a common signaling pathway chronically activated in degenerating retinas. TRIB3 has been recognized as a key mediator of the PERK UPR arm, influencing various metabolic pathways, such as insulin signaling, lipid metabolism, and glucose homeostasis, by acting as an AKT pseudokinase that prevents the activation of the AKT → mTOR axis. This study aimed to develop a gene-independent approach targeting the UPR TRIB3 mediator previously tested by our group using a genetic approach in mice with RD. The goal was to validate a therapeutic approach targeting TRIB3 interactomes through the pharmacological targeting of EGFR-TRIB3 and delivering cell-penetrating peptides targeting TRIB3 → AKT. The study employed rd10 and P23H RHO mice, with afatinib treatment conducted in p15 rd10 mice through daily intraperitoneal injections. P15 P23H RHO mice received intraocular injections of cell-penetrating peptides twice at a 2-week interval. Our study revealed that both strategies successfully targeted TRIB3 interactomes, leading to an improvement in scotopic A- and B-wave ERG recordings. Additionally, the afatinib-treated mice manifested enhanced photopic ERG amplitudes accompanied by a delay in photoreceptor cell loss. The treated rd10 retinas also showed increased PDE6β and RHO staining, along with an elevation in total PDE activity in the retinas. Consequently, our study demonstrated the feasibility of a gene-independent strategy to target common signaling in degenerating retinas by employing a TRIB3-based therapeutic approach that delays retinal function and photoreceptor cell loss in two RD models. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Retina Degeneration)

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22 pages, 20897 KiB

Open AccessArticle

Unveiling Drivers of Retinal Degeneration in RCS Rats: Functional, Morphological, and Molecular Insights

by Kabir Ahluwalia, Zhaodong Du, Juan Carlos Martinez-Camarillo, Aditya Naik, Biju B. Thomas, Dimitrios Pollalis, Sun Young Lee, Priyal Dave, Eugene Zhou, Zeyang Li, Catherine Chester, Mark S. Humayun and Stan G. Louie

Int. J. Mol. Sci. 2024, 25(7), 3749; https://doi.org/10.3390/ijms25073749 - 28 Mar 2024

Cited by 1 | Viewed by 2184

Abstract

Retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa, significantly contribute to adult blindness. The Royal College of Surgeons (RCS) rat is a well-established disease model for studying these dystrophies; however, molecular investigations remain limited. We conducted a comprehensive analysis of retinal degeneration in RCS rats, including an immunodeficient RCS (iRCS) sub-strain, using ocular coherence tomography, electroretinography, histology, and molecular dissection using transcriptomics and immunofluorescence. No significant differences in retinal degeneration progression were observed between the iRCS and immunocompetent RCS rats, suggesting a minimal role of adaptive immune responses in disease. Transcriptomic alterations were primarily in inflammatory signaling pathways, characterized by the strong upregulation of Tnfa, an inflammatory signaling molecule, and Nox1, a contributor to reactive oxygen species (ROS) generation. Additionally, a notable decrease in Alox15 expression was observed, pointing to a possible reduction in anti-inflammatory and pro-resolving lipid mediators. These findings were corroborated by immunostaining, which demonstrated increased photoreceptor lipid peroxidation (4HNE) and photoreceptor citrullination (CitH3) during retinal degeneration. Our work enhances the understanding of molecular changes associated with retinal degeneration in RCS rats and offers potential therapeutic targets within inflammatory and oxidative stress pathways for confirmatory research and development. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Retina Degeneration)

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