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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 (31 March 2024) | Viewed by 1923

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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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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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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

retina
retinal pigment epithelium
age-related macular degeneration
retinal degeneration

Published Papers (3 papers)

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Research

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

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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

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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

Viewed by 728

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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