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The Molecular and Cellular Basis of Retinal Diseases
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The Molecular and Cellular Basis of Retinal Diseases

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (1 March 2020) | Viewed by 85889

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Steven J. Pittler

E-Mail Website
Guest Editor
Departmentof Optometry and Vision Science, Vision Science Research Center, University of Alabama at Birmingham, Birmingham, AL, USA
Interests: photoreceptors; cyclic nucleotides; retinal degeneration; animal models; molecular neuroscience
Special Issues, Collections and Topics in MDPI journals
Prof. Steven J. Fliesler

E-Mail Website
Guest Editor
Departments of Ophthalmology and Biochemistry and the Neuroscience Graduate Program, The State University of New York (SUNY)—University at Buffalo, Buffalo, NY, USA
Interests: lipid metabolism; cholesterol; retinal degenerations; Smith-Lemli-Opitz; antioxidants

Special Issue Information

Dear Colleagues,

Recent success in the treatment of hereditary retinal disease caused by defects in the RPE65 gene and the FDA approval of this treatment has established the importance of the study of animal models and the translational impact of these research findings. This success has sparked an intense interest in the development of animal models for other hereditary eye diseases and has led to a dramatic increase in clinical trials in this area.

This Special Issue will focus on studies of new animal models of hereditary retinal degeneration and highlight the current knowledge in the field regarding the basic metabolic processes and biochemical pathways that offer promising new therapeutic targets for successful intervention in such retinal diseases. We hope that the combination of original papers and focused reviews will provide a useful resource for advancing an understanding of the molecular and cellular basis of retinal diseases, which will enlighten researchers currently in the field and entice some others to take a closer look at the great potential for discovery and intervention in hereditary diseases of the retina.

We look forward to your contributions.

Prof. Steven J Pittler
Prof. Steven J. Fliesler
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • retinal degeneration
  • animal models
  • photoreceptors
  • retinal metabolism

Published Papers (16 papers)

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Editorial

Jump to: Research, Review

6 pages, 202 KiB  
Editorial
Cells Special Issue: “The Molecular and Cellular Basis of Retinal Diseases”
by Steven J. Pittler and Steven J. Fliesler
Cells 2023, 12(15), 1933; https://doi.org/10.3390/cells12151933 - 26 Jul 2023
Viewed by 718
Abstract
The recent success in the treatment of hereditary retinal disease caused by defects in the RPE65 gene and the FDA approval of this treatment has established the importance of the study of animal models and the translational impact of these research findings [...] [...] Read more.
The recent success in the treatment of hereditary retinal disease caused by defects in the RPE65 gene and the FDA approval of this treatment has established the importance of the study of animal models and the translational impact of these research findings [...] Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)

Research

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17 pages, 6789 KiB  
Article
Diurnal Rhythmicity of Autophagy Is Impaired in the Diabetic Retina
by Xiaoping Qi, Sayak K. Mitter, Yuanqing Yan, Julia V Busik, Maria B Grant and Michael E Boulton
Cells 2020, 9(4), 905; https://doi.org/10.3390/cells9040905 - 7 Apr 2020
Cited by 36 | Viewed by 3273
Abstract
Retinal homeostasis is under both diurnal and circadian regulation. We sought to investigate the diurnal expression of autophagy proteins in normal rodent retina and to determine if this is impaired in diabetic retinopathy. C57BL/6J mice and Bio-Breeding Zucker (BBZ) rats were maintained under [...] Read more.
Retinal homeostasis is under both diurnal and circadian regulation. We sought to investigate the diurnal expression of autophagy proteins in normal rodent retina and to determine if this is impaired in diabetic retinopathy. C57BL/6J mice and Bio-Breeding Zucker (BBZ) rats were maintained under a 12h/12h light/dark cycle and eyes, enucleated over a 24 h period. Eyes were also collected from diabetic mice with two or nine-months duration of type 1 diabetes (T1D) and Bio-Breeding Zucker diabetic rat (BBZDR/wor rats with 4-months duration of type 2 diabetes (T2D). Immunohistochemistry was performed for the autophagy proteins Atg7, Atg9, LC3 and Beclin1. These autophagy proteins (Atgs) were abundantly expressed in neural retina and endothelial cells in both mice and rats. A differential staining pattern was observed across the retinas which demonstrated a distinctive diurnal rhythmicity. All Atgs showed localization to retinal blood vessels with Atg7 being the most highly expressed. Analysis of the immunostaining demonstrated distinctive diurnal rhythmicity, of which Atg9 and LC3 shared a biphasic expression cycle with the highest level at 8:15 am and 8:15 pm. In contrast, Beclin1 revealed a 24-h cycle with the highest level observed at midnight. Atg7 was also on a 24-h cycle with peak expression at 8:15am, coinciding with the first peak expression of Atg9 and LC3. In diabetic animals, there was a dramatic reduction in all four Atgs and the distinctive diurnal rhythmicity of these autophagy proteins was significantly impaired and phase shifted in both T1D and T2D animals. Restoration of diurnal rhythmicity and facilitation of autophagy protein expression may provide new treatment strategies for diabetic retinopathy. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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11 pages, 3360 KiB  
Article
Lack of Overt Retinal Degeneration in a K42E Dhdds Knock-In Mouse Model of RP59
by Sriganesh Ramachandra Rao, Steven J. Fliesler, Pravallika Kotla, Mai N. Nguyen and Steven J. Pittler
Cells 2020, 9(4), 896; https://doi.org/10.3390/cells9040896 - 7 Apr 2020
Cited by 9 | Viewed by 5700
Abstract
Dehydrodolichyl diphosphate synthase (DHDDS) is required for protein N-glycosylation in eukaryotic cells. A K42E point mutation in the DHDDS gene causes an autosomal recessive form of retinitis pigmentosa (RP59), which has been classified as a congenital disease of glycosylation (CDG). We generated [...] Read more.
Dehydrodolichyl diphosphate synthase (DHDDS) is required for protein N-glycosylation in eukaryotic cells. A K42E point mutation in the DHDDS gene causes an autosomal recessive form of retinitis pigmentosa (RP59), which has been classified as a congenital disease of glycosylation (CDG). We generated K42E Dhdds knock-in mice as a potential model for RP59. Mice heterozygous for the Dhdds K42E mutation were generated using CRISPR/Cas9 technology and crossed to generate DhddsK42E/K42E homozygous mice. Spectral domain-optical coherence tomography (SD-OCT) was performed to assess retinal structure, relative to age-matched wild type (WT) controls. Immunohistochemistry against glial fibrillary acidic protein (GFAP) and opsin (1D4 epitope) was performed on retinal frozen sections to monitor gliosis and opsin localization, respectively, while lectin cytochemistry, plus and minus PNGase-F treatment, was performed to assess protein glycosylation status. Retinas of DhddsK42E/K42E mice exhibited grossly normal histological organization from 1 to 12 months of age. Anti-GFAP immunoreactivity was markedly increased in DhddsK42E/K42E mice, relative to controls. However, opsin immunolocalization, ConA labeling and PNGase-F sensitivity were comparable in mutant and control retinas. Hence, retinas of DhddsK42E/K42E mice exhibited no overt signs of degeneration, yet were markedly gliotic, but without evidence of compromised protein N-glycosylation. These results challenge the notion of RP59 as a DHDDS loss-of-function CDG and highlight the need to investigate unexplored RP59 disease mechanisms. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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13 pages, 4270 KiB  
Article
Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration
by Marci L. DeRamus, Stephanie J. Davis, Sriganesh Ramachandra Rao, Cyril Nyankerh, Delores Stacks, Timothy W. Kraft, Steven J. Fliesler and Steven J. Pittler
Cells 2020, 9(3), 771; https://doi.org/10.3390/cells9030771 - 21 Mar 2020
Cited by 10 | Viewed by 5502
Abstract
Patients with certain defects in the dehydrodolichyl diphosphate synthase (DHDDS) gene (RP59; OMIM #613861) exhibit classic symptoms of retinitis pigmentosa, as well as macular changes, suggestive of retinal pigment epithelium (RPE) involvement. The DHDDS enzyme is ubiquitously required for several pathways of protein [...] Read more.
Patients with certain defects in the dehydrodolichyl diphosphate synthase (DHDDS) gene (RP59; OMIM #613861) exhibit classic symptoms of retinitis pigmentosa, as well as macular changes, suggestive of retinal pigment epithelium (RPE) involvement. The DHDDS enzyme is ubiquitously required for several pathways of protein glycosylation. We wish to understand the basis for selective ocular pathology associated with certain DHDDS mutations and the contribution of specific ocular cell types to the pathology of mutant Dhdds-mediated retinal degeneration. To circumvent embryonic lethality associated with Dhdds knockout, we generated a Cre-dependent knockout allele of murine Dhdds (Dhddsflx/flx). We used targeted Cre expression to study the importance of the enzyme in the RPE. Structural alterations of the RPE and retina including reduction in outer retinal thickness, cell layer disruption, and increased RPE hyper-reflectivity were apparent at one postnatal month. At three months, RPE and photoreceptor disruption was observed non-uniformly across the retina as well as RPE transmigration into the photoreceptor layer, external limiting membrane descent towards the RPE, and patchy loss of photoreceptors. Functional loss measured by electroretinography was consistent with structural loss showing scotopic a- and b-wave reductions of 83% and 77%, respectively, at three months. These results indicate that RPE dysfunction contributes to DHDDS mutation-mediated pathology and suggests a more complicated disease mechanism than simply disruption of glycosylation. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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12 pages, 4347 KiB  
Article
Innate and Autoimmunity in the Pathogenesis of Inherited Retinal Dystrophy
by T. J. Hollingsworth and Alecia K. Gross
Cells 2020, 9(3), 630; https://doi.org/10.3390/cells9030630 - 5 Mar 2020
Cited by 12 | Viewed by 2683
Abstract
Inherited retinal dystrophies (RDs) are heterogenous in many aspects including genes involved, age of onset, rate of progression, and treatments. While RDs are caused by a plethora of different mutations, all result in the same outcome of blindness. While treatments, both gene therapy-based [...] Read more.
Inherited retinal dystrophies (RDs) are heterogenous in many aspects including genes involved, age of onset, rate of progression, and treatments. While RDs are caused by a plethora of different mutations, all result in the same outcome of blindness. While treatments, both gene therapy-based and drug-based, have been developed to slow or halt disease progression and prevent further blindness, only a small handful of the forms of RDs have treatments available, which are primarily for recessively inherited forms. Using immunohistochemical methods coupled with electroretinography, optical coherence tomography, and fluorescein angiography, we show that in rhodopsin mutant mice, the involvement of both the innate and the autoimmune systems could be a strong contributing factor in disease progression and pathogenesis. Herein, we show that monocytic phagocytosis and inflammatory cytokine release along with protein citrullination, a major player in forms of autoimmunity, work to enhance the progression of RD associated with a rhodopsin mutation. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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15 pages, 5415 KiB  
Article
Role of FGF and Hyaluronan in Choroidal Neovascularization in Sorsby Fundus Dystrophy
by Alyson Wolk, Dilara Hatipoglu, Alecia Cutler, Mariya Ali, Lestella Bell, Jian Hua Qi, Rupesh Singh, Julia Batoki, Laura Karle, Vera L. Bonilha, Oliver Wessely, Heidi Stoehr, Vincent Hascall and Bela Anand-Apte
Cells 2020, 9(3), 608; https://doi.org/10.3390/cells9030608 - 4 Mar 2020
Cited by 4 | Viewed by 4321
Abstract
Sorsby’s fundus dystrophy (SFD) is an inherited blinding disorder caused by mutations in the tissue inhibitor of metalloproteinase-3 (TIMP3) gene. The SFD pathology of macular degeneration with subretinal deposits and choroidal neovascularization (CNV) closely resembles that of the more common age-related [...] Read more.
Sorsby’s fundus dystrophy (SFD) is an inherited blinding disorder caused by mutations in the tissue inhibitor of metalloproteinase-3 (TIMP3) gene. The SFD pathology of macular degeneration with subretinal deposits and choroidal neovascularization (CNV) closely resembles that of the more common age-related macular degeneration (AMD). The objective of this study was to gain further insight into the molecular mechanism(s) by which mutant TIMP3 induces CNV. In this study we demonstrate that hyaluronan (HA), a large glycosaminoglycan, is elevated in the plasma and retinal pigment epithelium (RPE)/choroid of patients with AMD. Mice carrying the S179C-TIMP3 mutation also showed increased plasma levels of HA as well as accumulation of HA around the RPE in the retina. Human RPE cells expressing the S179C-TIMP3 mutation accumulated HA apically, intracellularly and basally when cultured long-term compared with cells expressing wildtype TIMP3. We recently reported that RPE cells carrying the S179C-TIMP3 mutation have the propensity to induce angiogenesis via basic fibroblast growth factor (FGF-2). We now demonstrate that FGF-2 induces accumulation of HA in RPE cells. These results suggest that the TIMP3-MMP-FGF-2-HA axis may have an important role in the pathogenesis of CNV in SFD and possibly AMD. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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18 pages, 48585 KiB  
Article
Characterizing the Retinal Phenotype in the High-Fat Diet and Western Diet Mouse Models of Prediabetes
by Bright Asare-Bediako, Sunil K. Noothi, Sergio Li Calzi, Baskaran Athmanathan, Cristiano P. Vieira, Yvonne Adu-Agyeiwaah, Mariana Dupont, Bryce A. Jones, Xiaoxin X. Wang, Dibyendu Chakraborty, Moshe Levi, Prabhakara R. Nagareddy and Maria B. Grant
Cells 2020, 9(2), 464; https://doi.org/10.3390/cells9020464 - 18 Feb 2020
Cited by 30 | Viewed by 4967
Abstract
We sought to delineate the retinal features associated with the high-fat diet (HFD) mouse, a widely used model of obesity. C57BL/6 mice were fed either a high-fat (60% fat; HFD) or low-fat (10% fat; LFD) diet for up to 12 months. The effect [...] Read more.
We sought to delineate the retinal features associated with the high-fat diet (HFD) mouse, a widely used model of obesity. C57BL/6 mice were fed either a high-fat (60% fat; HFD) or low-fat (10% fat; LFD) diet for up to 12 months. The effect of HFD on body weight and insulin resistance were measured. The retina was assessed by electroretinogram (ERG), fundus photography, permeability studies, and trypsin digests for enumeration of acellular capillaries. The HFD cohort experienced hypercholesterolemia when compared to the LFD cohort, but not hyperglycemia. HFD mice developed a higher body weight (60.33 g vs. 30.17g, p < 0.0001) as well as a reduced insulin sensitivity index (9.418 vs. 62.01, p = 0.0002) compared to LFD controls. At 6 months, retinal functional testing demonstrated a reduction in a-wave and b-wave amplitudes. At 12 months, mice on HFD showed evidence of increased retinal nerve infarcts and vascular leakage, reduced vascular density, but no increase in number of acellular capillaries compared to LFD mice. In conclusion, the HFD mouse is a useful model for examining the effect of prediabetes and hypercholesterolemia on the retina. The HFD-induced changes appear to occur slower than those observed in type 2 diabetes (T2D) models but are consistent with other retinopathy models, showing neural damage prior to vascular changes. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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14 pages, 3177 KiB  
Article
Single-Cell RNA Sequencing in Human Retinal Degeneration Reveals Distinct Glial Cell Populations
by Andrew P. Voigt, Elaine Binkley, Miles J. Flamme-Wiese, Shemin Zeng, Adam P. DeLuca, Todd E. Scheetz, Budd A. Tucker, Robert F. Mullins and Edwin M. Stone
Cells 2020, 9(2), 438; https://doi.org/10.3390/cells9020438 - 13 Feb 2020
Cited by 35 | Viewed by 5888
Abstract
Degenerative diseases affecting retinal photoreceptor cells have numerous etiologies and clinical presentations. We clinically and molecularly studied the retina of a 70-year-old patient with retinal degeneration attributed to autoimmune retinopathy. The patient was followed for 19 years for progressive peripheral visual field loss [...] Read more.
Degenerative diseases affecting retinal photoreceptor cells have numerous etiologies and clinical presentations. We clinically and molecularly studied the retina of a 70-year-old patient with retinal degeneration attributed to autoimmune retinopathy. The patient was followed for 19 years for progressive peripheral visual field loss and pigmentary changes. Single-cell RNA sequencing was performed on foveal and peripheral retina from this patient and four control patients, and cell-specific gene expression differences were identified between healthy and degenerating retina. Distinct populations of glial cells, including astrocytes and Müller cells, were identified in the tissue from the retinal degeneration patient. The glial cell populations demonstrated an expression profile consistent with reactive gliosis. This report provides evidence that glial cells have a distinct transcriptome in the setting of human retinal degeneration and represents a complementary clinical and molecular investigation of a case of progressive retinal disease. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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Review

Jump to: Editorial, Research

12 pages, 2012 KiB  
Review
Effects of Mitochondrial-Derived Peptides (MDPs) on Mitochondrial and Cellular Health in AMD
by Sonali Nashine and M. Cristina Kenney
Cells 2020, 9(5), 1102; https://doi.org/10.3390/cells9051102 - 29 Apr 2020
Cited by 25 | Viewed by 6559
Abstract
Substantive evidence demonstrates the contribution of mitochondrial dysfunction in the etiology and pathogenesis of Age-related Macular Degeneration (AMD). Recently, extensive characterization of Mitochondrial-Derived Peptides (MDPs) has revealed their cytoprotective role in several diseases, including AMD. Here we summarize the varied effects of MDPs [...] Read more.
Substantive evidence demonstrates the contribution of mitochondrial dysfunction in the etiology and pathogenesis of Age-related Macular Degeneration (AMD). Recently, extensive characterization of Mitochondrial-Derived Peptides (MDPs) has revealed their cytoprotective role in several diseases, including AMD. Here we summarize the varied effects of MDPs on cellular and mitochondrial health, which establish the merit of MDPs as therapeutic targets for AMD. We argue that further research to delve into the mechanisms of action and delivery of MDPs may advance the field of AMD therapy. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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67 pages, 5537 KiB  
Review
Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss
by Gayle B. Collin, Navdeep Gogna, Bo Chang, Nattaya Damkham, Jai Pinkney, Lillian F. Hyde, Lisa Stone, Jürgen K. Naggert, Patsy M. Nishina and Mark P. Krebs
Cells 2020, 9(4), 931; https://doi.org/10.3390/cells9040931 - 10 Apr 2020
Cited by 49 | Viewed by 11935
Abstract
Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie [...] Read more.
Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. The progression of PR cell loss with postnatal age was documented in mutant alleles of genes grouped by biological function. As anticipated, a wide range in the onset and rate of cell loss was observed among the reported models. The analysis underscored relationships between RD genes and ciliary function, transcription-coupled DNA damage repair, and cellular chloride homeostasis. Comparing the mouse gene list to human RD genes identified in the RetNet database revealed that mouse models are available for 40% of the known human diseases, suggesting opportunities for future research. This work may provide insight into the molecular players and pathways through which PR degenerative disease occurs and may be useful for planning translational studies. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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28 pages, 775 KiB  
Review
Large Animal Models of Inherited Retinal Degenerations: A Review
by Paige A. Winkler, Laurence M. Occelli and Simon M. Petersen-Jones
Cells 2020, 9(4), 882; https://doi.org/10.3390/cells9040882 - 3 Apr 2020
Cited by 47 | Viewed by 5722
Abstract
Studies utilizing large animal models of inherited retinal degeneration (IRD) have proven important in not only the development of translational therapeutic approaches, but also in improving our understanding of disease mechanisms. The dog is the predominant species utilized because spontaneous IRD is common [...] Read more.
Studies utilizing large animal models of inherited retinal degeneration (IRD) have proven important in not only the development of translational therapeutic approaches, but also in improving our understanding of disease mechanisms. The dog is the predominant species utilized because spontaneous IRD is common in the canine pet population. Cats are also a source of spontaneous IRDs. Other large animal models with spontaneous IRDs include sheep, horses and non-human primates (NHP). The pig has also proven valuable due to the ease in which transgenic animals can be generated and work is ongoing to produce engineered models of other large animal species including NHP. These large animal models offer important advantages over the widely used laboratory rodent models. The globe size and dimensions more closely parallel those of humans and, most importantly, they have a retinal region of high cone density and denser photoreceptor packing for high acuity vision. Laboratory rodents lack such a retinal region and, as macular disease is a critical cause for vision loss in humans, having a comparable retinal region in model species is particularly important. This review will discuss several large animal models which have been used to study disease mechanisms relevant for the equivalent human IRD. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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17 pages, 729 KiB  
Review
Phosphoinositides in Retinal Function and Disease
by Theodore G. Wensel
Cells 2020, 9(4), 866; https://doi.org/10.3390/cells9040866 - 2 Apr 2020
Cited by 19 | Viewed by 4573
Abstract
Phosphatidylinositol and its phosphorylated derivatives, the phosphoinositides, play many important roles in all eukaryotic cells. These include modulation of physical properties of membranes, activation or inhibition of membrane-associated proteins, recruitment of peripheral membrane proteins that act as effectors, and control of membrane trafficking. [...] Read more.
Phosphatidylinositol and its phosphorylated derivatives, the phosphoinositides, play many important roles in all eukaryotic cells. These include modulation of physical properties of membranes, activation or inhibition of membrane-associated proteins, recruitment of peripheral membrane proteins that act as effectors, and control of membrane trafficking. They also serve as precursors for important second messengers, inositol (1,4,5) trisphosphate and diacylglycerol. Animal models and human diseases involving defects in phosphoinositide regulatory pathways have revealed their importance for function in the mammalian retina and retinal pigmented epithelium. New technologies for localizing, measuring and genetically manipulating them are revealing new information about their importance for the function and health of the vertebrate retina. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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25 pages, 3673 KiB  
Review
The Interplay between Peripherin 2 Complex Formation and Degenerative Retinal Diseases
by Lars Tebbe, Mashal Kakakhel, Mustafa S. Makia, Muayyad R. Al-Ubaidi and Muna I. Naash
Cells 2020, 9(3), 784; https://doi.org/10.3390/cells9030784 - 24 Mar 2020
Cited by 12 | Viewed by 4009
Abstract
Peripherin 2 (Prph2) is a photoreceptor-specific tetraspanin protein present in the outer segment (OS) rims of rod and cone photoreceptors. It shares many common features with other tetraspanins, including a large intradiscal loop which contains several cysteines. This loop enables Prph2 to associate [...] Read more.
Peripherin 2 (Prph2) is a photoreceptor-specific tetraspanin protein present in the outer segment (OS) rims of rod and cone photoreceptors. It shares many common features with other tetraspanins, including a large intradiscal loop which contains several cysteines. This loop enables Prph2 to associate with itself to form homo-oligomers or with its homologue, rod outer segment membrane protein 1 (Rom1) to form hetero-tetramers and hetero-octamers. Mutations in PRPH2 cause a multitude of retinal diseases including autosomal dominant retinitis pigmentosa (RP) or cone dominant macular dystrophies. The importance of Prph2 for photoreceptor development, maintenance and function is underscored by the fact that its absence results in a failure to initialize OS formation in rods and formation of severely disorganized OS membranous structures in cones. Although the exact role of Rom1 has not been well studied, it has been concluded that it is not necessary for disc morphogenesis but is required for fine tuning OS disc size and structure. Pathogenic mutations in PRPH2 often result in complex and multifactorial phenotypes, involving not just photoreceptors, as has historically been reasoned, but also secondary effects on the retinal pigment epithelium (RPE) and retinal/choroidal vasculature. The ability of Prph2 to form complexes was identified as a key requirement for the development and maintenance of OS structure and function. Studies using mouse models of pathogenic Prph2 mutations established a connection between changes in complex formation and disease phenotypes. Although progress has been made in the development of therapeutic approaches for retinal diseases in general, the highly complex interplay of functions mediated by Prph2 and the precise regulation of these complexes made it difficult, thus far, to develop a suitable Prph2-specific therapy. Here we describe the latest results obtained in Prph2-associated research and how mouse models provided new insights into the pathogenesis of its related diseases. Furthermore, we give an overview on the current status of the development of therapeutic solutions. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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29 pages, 1644 KiB  
Review
From Rust to Quantum Biology: The Role of Iron in Retina Physiopathology
by Emilie Picard, Alejandra Daruich, Jenny Youale, Yves Courtois and Francine Behar-Cohen
Cells 2020, 9(3), 705; https://doi.org/10.3390/cells9030705 - 13 Mar 2020
Cited by 31 | Viewed by 7262
Abstract
Iron is essential for cell survival and function. It is a transition metal, that could change its oxidation state from Fe2+ to Fe3+ involving an electron transfer, the key of vital functions but also organ dysfunctions. The goal of this review [...] Read more.
Iron is essential for cell survival and function. It is a transition metal, that could change its oxidation state from Fe2+ to Fe3+ involving an electron transfer, the key of vital functions but also organ dysfunctions. The goal of this review is to illustrate the primordial role of iron and local iron homeostasis in retinal physiology and vision, as well as the pathological consequences of iron excess in animal models of retinal degeneration and in human retinal diseases. We summarize evidence of the potential therapeutic effect of iron chelation in retinal diseases and especially the interest of transferrin, a ubiquitous endogenous iron-binding protein, having the ability to treat or delay degenerative retinal diseases. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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23 pages, 2837 KiB  
Review
Noble Metals and Soft Bio-Inspired Nanoparticles in Retinal Diseases Treatment: A Perspective
by Valeria De Matteis and Loris Rizzello
Cells 2020, 9(3), 679; https://doi.org/10.3390/cells9030679 - 10 Mar 2020
Cited by 34 | Viewed by 6907
Abstract
We are witnessing an exponential increase in the use of different nanomaterials in a plethora of biomedical fields. We are all aware of how nanoparticles (NPs) have influenced and revolutionized the way we supply drugs or how to use them as therapeutic agents [...] Read more.
We are witnessing an exponential increase in the use of different nanomaterials in a plethora of biomedical fields. We are all aware of how nanoparticles (NPs) have influenced and revolutionized the way we supply drugs or how to use them as therapeutic agents thanks to their tunable physico-chemical properties. However, there is still a niche of applications where NP have not yet been widely explored. This is the field of ocular delivery and NP-based therapy, which characterizes the topic of the current review. In particular, many efforts are being made to develop nanosystems capable of reaching deeper sections of the eye such as the retina. Particular attention will be given here to noble metal (gold and silver), and to polymeric nanoparticles, systems consisting of lipid bilayers such as liposomes or vesicles based on nonionic surfactant. We will report here the most relevant literature on the use of different types of NPs for an efficient delivery of drugs and bio-macromolecules to the eyes or as active therapeutic tools. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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13 pages, 1168 KiB  
Review
The Intersection of Serine Metabolism and Cellular Dysfunction in Retinal Degeneration
by Tirthankar Sinha, Larissa Ikelle, Muna I. Naash and Muayyad R. Al-Ubaidi
Cells 2020, 9(3), 674; https://doi.org/10.3390/cells9030674 - 10 Mar 2020
Cited by 22 | Viewed by 4569
Abstract
In the past, the importance of serine to pathologic or physiologic anomalies was inadequately addressed. Omics research has significantly advanced in the last two decades, and metabolomic data of various tissues has finally brought serine metabolism to the forefront of metabolic research, primarily [...] Read more.
In the past, the importance of serine to pathologic or physiologic anomalies was inadequately addressed. Omics research has significantly advanced in the last two decades, and metabolomic data of various tissues has finally brought serine metabolism to the forefront of metabolic research, primarily for its varied role throughout the central nervous system. The retina is one of the most complex neuronal tissues with a multitude of functions. Although recent studies have highlighted the importance of free serine and its derivatives to retinal homeostasis, currently few reviews exist that comprehensively analyze the topic. Here, we address this gap by emphasizing how and why the de novo production and demand for serine is exceptionally elevated in the retina. Many basic physiological functions of the retina require serine. Serine-derived sphingolipids and phosphatidylserine for phagocytosis by the retinal pigment epithelium (RPE) and neuronal crosstalk of the inner retina via D-serine require proper serine metabolism. Moreover, serine is involved in sphingolipid–ceramide balance for both the outer retina and the RPE and the reductive currency generation for the RPE via serine biosynthesis. Finally and perhaps the most vital part of serine metabolism is free radical scavenging in the entire retina via serine-derived scavengers like glycine and GSH. It is hard to imagine that a single tissue could have such a broad and extensive dependency on serine homeostasis. Any dysregulation in serine mechanisms can result in a wide spectrum of retinopathies. Therefore, most critically, this review provides a strong argument for the exploration of serine-based clinical interventions for retinal pathologies. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Retinal Diseases)
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