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Molecular Biology of Age-Related Macular Degeneration (AMD)

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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 (15 October 2018) | Viewed by 73817

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Prof. Dr. Janusz Blasiak

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Faculty of Biology and Environmental Sciences, Department of Molecular Genetics, University of Lodz, 90-136 Lodz, Poland
Interests: DNA and RNA structure; DNA damage and repair; DNA damage response; mutagenesis; cancer transformation; age-related macular degeneration; autophagy; mitochondrial quality control; mitophagy; miRNA-lncRNA regulation; gene regulation; epigenetics
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Prof. Dr. Kai Kaarniranta

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Department of Ophthalmology, Kuopio University Hospital, 70211 Kuopio, Finland
Interests: aging; autophagy; eye diseases; genetics; macula; oxidative stress; proteolysis; retinal pigment epithelium
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Dear Colleagues,

Age-related macular degeneration (AMD) is the main cause of blindness in the elderly in developed countries, and is an emerging health and social problem, as the number of individuals affected by AMD in 2020 is estimated to reach about 200 million. Therefore, AMD is an important element of the global issue of vision loss. Additionally, there is no efficient treatment in most AMD cases. AMD is a complex disease that associates with aging and several genetic and environmental risk factors. Cellular reaction to oxidative stress, senescence, autophagy, inflammatory response, and DNA damage reaction are frequently reported to be impaired in AMD, but causative relationships between AMD and these effects are not completely clear. Therefore, studies on the molecular mechanisms of AMD pathogenesis are justified and can bring results important regarding its biology and therapy.

This Special Issue welcomes both original papers and review articles addressing one or several of the above-mentioned issues, or of the topics mentioned in the keywords listed below.

Prof. Dr. Janusz Blasiak
Prof. Dr. Kai Kaarniranta
Guest Editors

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Keywords

AMD pathogenesis
Retinal pigment epithelium, photoreceptors and choriocapillaris in AMD
Oxidative stress and antioxidant system in AMD
Senescence and organismal aging in AMD
Mitochondrial quality control in AMD
Autophagy and mitophagy in AMD
DNA damage reaction in the nucleus and mitochondria in retinal pigment epithelium
DNA damage and repair in AMD
AMD genetics: mutations and polymorphisms of genes related to AMD
AMD epigenetics
Programmed cell death, including apoptosis, pyroptosis and necroptosis in ertinal pigment epithelium
Inflammation and the inflammasome activation
miRNA-lncRNA regulation in AMD
Neurodegenerative diseases related to AMD
Models to study AMD pathogenesis

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Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0 in International Journal of Molecular Sciences (18 articles)

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20 pages, 2483 KiB

Open AccessReview

PGC-1α Protects RPE Cells of the Aging Retina against Oxidative Stress-Induced Degeneration through the Regulation of Senescence and Mitochondrial Quality Control. The Significance for AMD Pathogenesis

by Kai Kaarniranta, Jakub Kajdanek, Jan Morawiec, Elzbieta Pawlowska and Janusz Blasiak

Int. J. Mol. Sci. 2018, 19(8), 2317; https://doi.org/10.3390/ijms19082317 - 7 Aug 2018

Cited by 99 | Viewed by 10374

Abstract

PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is a transcriptional coactivator of many genes involved in energy management and mitochondrial biogenesis. PGC-1α expression is associated with cellular senescence, organismal aging, and many age-related diseases, including AMD (age-related macular degeneration), an important global issue concerning vision loss. We and others have developed a model of AMD pathogenesis, in which stress-induced senescence of retinal pigment epithelium (RPE) cells leads to AMD-related pathological changes. PGC-1α can decrease oxidative stress, a key factor of AMD pathogenesis related to senescence, through upregulation of antioxidant enzymes and DNA damage response. PGC-1α is an important regulator of VEGF (vascular endothelial growth factor), which is targeted in the therapy of wet AMD, the most devastating form of AMD. Dysfunction of mitochondria induces cellular senescence associated with AMD pathogenesis. PGC-1α can improve mitochondrial biogenesis and negatively regulate senescence, although this function of PGC-1α in AMD needs further studies. Post-translational modifications of PGC-1α by AMPK (AMP kinase) and SIRT1 (sirtuin 1) are crucial for its activation and important in AMD pathogenesis. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD))

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16 pages, 2006 KiB

Open AccessReview

The Controversial Role of TGF-β in Neovascular Age-Related Macular Degeneration Pathogenesis

by Gian Marco Tosi, Maurizio Orlandini and Federico Galvagni

Int. J. Mol. Sci. 2018, 19(11), 3363; https://doi.org/10.3390/ijms19113363 - 27 Oct 2018

Cited by 50 | Viewed by 8751

Abstract

The multifunctional transforming growth factors-beta (TGF-βs) have been extensively studied regarding their role in the pathogenesis of neovascular age-related macular degeneration (nAMD), a major cause of severe visual loss in the elderly in developed countries. Despite this, their effect remains somewhat controversial. Indeed, both pro- and antiangiogenic activities have been suggested for TGF-β signaling in the development and progression of nAMD, and opposite therapies have been proposed targeting the inhibition or activation of the TGF-β pathway. The present article summarizes the current literature linking TGF-β and nAMD, and reviews experimental data supporting both pro- and antiangiogenic hypotheses, taking into account the limitations of the experimental approaches. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD))

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15 pages, 2565 KiB

Open AccessReview

The Question of a Role for Statins in Age-Related Macular Degeneration

by Marina Roizenblatt, Nara Naranjit, Mauricio Maia and Peter L. Gehlbach

Int. J. Mol. Sci. 2018, 19(11), 3688; https://doi.org/10.3390/ijms19113688 - 21 Nov 2018

Cited by 23 | Viewed by 5519

Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss in patients over the age of 65 years in industrialized countries. Epidemiologic studies suggest that high dietary fat intake is a risk factor for the development and progression of both vascular and retinal disease. These, and other associations, suggest a hypothesis linking elevated cholesterol and AMD progression. It follows, therefore, that cholesterol-lowering medications, such as statins, may influence the onset and progression of AMD. However, the findings have been inconclusive as to whether statins play a role in AMD. Due to the significant public health implications of a potential inhibitory effect of statins on the onset and progression of AMD, it is important to continually evaluate emerging findings germane to this question. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD))

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23 pages, 2364 KiB

Open AccessReview

Interplay between Autophagy and the Ubiquitin-Proteasome System and Its Role in the Pathogenesis of Age-Related Macular Degeneration

by Janusz Blasiak, Elzbieta Pawlowska, Joanna Szczepanska and Kai Kaarniranta

Int. J. Mol. Sci. 2019, 20(1), 210; https://doi.org/10.3390/ijms20010210 - 8 Jan 2019

Cited by 101 | Viewed by 10996

Abstract

Age-related macular degeneration (AMD) is a complex eye disease with many pathogenesis factors, including defective cellular waste management in retinal pigment epithelium (RPE). Main cellular waste in AMD are: all-trans retinal, drusen and lipofuscin, containing unfolded, damaged and unneeded proteins, which are degraded and recycled in RPE cells by two main machineries—the ubiquitin-proteasome system (UPS) and autophagy. Recent findings show that these systems can act together with a significant role of the EI24 (etoposide-induced protein 2.4 homolog) ubiquitin ligase in their action. On the other hand, E3 ligases are essential in both systems, but E3 is degraded by autophagy. The interplay between UPS and autophagy was targeted in several diseases, including Alzheimer disease. Therefore, cellular waste clearing in AMD should be considered in the context of such interplay rather than either of these systems singly. Aging and oxidative stress, two major AMD risk factors, reduce both UPS and autophagy. In conclusion, molecular mechanisms of UPS and autophagy can be considered as a target in AMD prevention and therapeutic perspective. Further work is needed to identify molecules and effects important for the coordination of action of these two cellular waste management systems. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD))

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20 pages, 1152 KiB

Open AccessReview

Is Retinal Metabolic Dysfunction at the Center of the Pathogenesis of Age-related Macular Degeneration?

by Thierry Léveillard, Nancy J. Philp and Florian Sennlaub

Int. J. Mol. Sci. 2019, 20(3), 762; https://doi.org/10.3390/ijms20030762 - 11 Feb 2019

Cited by 73 | Viewed by 7511

Abstract

The retinal pigment epithelium (RPE) forms the outer blood–retina barrier and facilitates the transepithelial transport of glucose into the outer retina via GLUT1. Glucose is metabolized in photoreceptors via the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS) but also by aerobic glycolysis to generate glycerol for the synthesis of phospholipids for the renewal of their outer segments. Aerobic glycolysis in the photoreceptors also leads to a high rate of production of lactate which is transported out of the subretinal space to the choroidal circulation by the RPE. Lactate taken up by the RPE is converted to pyruvate and metabolized via OXPHOS. Excess lactate in the RPE is transported across the basolateral membrane to the choroid. The uptake of glucose by cone photoreceptor cells is enhanced by rod-derived cone viability factor (RdCVF) secreted by rods and by insulin signaling. Together, the three cells act as symbiotes: the RPE supplies the glucose from the choroidal circulation to the photoreceptors, the rods help the cones, and both produce lactate to feed the RPE. In age-related macular degeneration this delicate ménage à trois is disturbed by the chronic infiltration of inflammatory macrophages. These immune cells also rely on aerobic glycolysis and compete for glucose and produce lactate. We here review the glucose metabolism in the homeostasis of the outer retina and in macrophages and hypothesize what happens when the metabolism of photoreceptors and the RPE is disturbed by chronic inflammation. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD))

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20 pages, 2539 KiB

Open AccessArticle

Human Embryonic Stem Cell-Derived Retinal Pigment Epithelium-Role in Dead Cell Clearance and Inflammation

by Mária Szatmári-Tóth, Tanja Ilmarinen, Alexandra Mikhailova, Heli Skottman, Anu Kauppinen, Kai Kaarniranta, Endre Kristóf, Lyubomyr Lytvynchuk, Zoltán Veréb, László Fésüs and Goran Petrovski

Int. J. Mol. Sci. 2019, 20(4), 926; https://doi.org/10.3390/ijms20040926 - 20 Feb 2019

Cited by 20 | Viewed by 5030

Abstract

Inefficient removal of dying retinal pigment epithelial (RPE) cells by professional phagocytes can result in debris formation and development of age-related macular degeneration (AMD). Chronic oxidative stress and inflammation play an important role in AMD pathogenesis. Only a few well-established in vitro phagocytosis assay models exist. We propose human embryonic stem cell-derived-RPE cells as a new model for studying RPE cell removal by professional phagocytes. The characteristics of human embryonic stem cells-derived RPE (hESC-RPE) are similar to native RPEs based on their gene and protein expression profile, integrity, and barrier properties or regarding drug transport. However, no data exist about RPE death modalities and how efficiently dying hESC-RPEs are taken upby macrophages, and whether this process triggers an inflammatory responses. This study demonstrates hESC-RPEs can be induced to undergo anoikis or autophagy-associated cell death due to extracellular matrix detachment or serum deprivation and hydrogen-peroxide co-treatment, respectively, similar to primary human RPEs. Dying hESC-RPEs are efficiently engulfed by macrophages which results in high amounts of IL-6 and IL-8 cytokine release. These findings suggest that the clearance of anoikic and autophagy-associated dying hESC-RPEs can be used as a new model for investigating AMD pathogenesis or for testing the in vivo potential of these cells in stem cell therapy. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD))

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11 pages, 1492 KiB

Open AccessArticle

The Interplay between miRNA-Related Variants and Age-Related Macular Degeneration: EVIDENCE of Association of MIR146A and MIR27A

by Claudia Strafella, Valeria Errichiello, Valerio Caputo, Gianluca Aloe, Federico Ricci, Andrea Cusumano, Giuseppe Novelli, Emiliano Giardina and Raffaella Cascella

Int. J. Mol. Sci. 2019, 20(7), 1578; https://doi.org/10.3390/ijms20071578 - 29 Mar 2019

Cited by 14 | Viewed by 3449

Abstract

The complex interplay among genetic, epigenetic, and environmental variables is the basis for the multifactorial origin of age-related macular degeneration (AMD). Previous results highlighted that single nucleotide polymorphisms (SNPs) of CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA, and COL8A1 were significantly associated with the risk of AMD in the Italian population. Given these data, this study aimed to investigate the impact of SNPs in genes coding for MIR146A, MIR31, MIR23A, MIR27A, MIR20A, and MIR150 on their susceptibility to AMD. Nine-hundred and seventy-six patients with exudative AMD and 1000 controls were subjected to an epigenotyping analysis through real-time PCR and direct sequencing. Biostatistical and bioinformatic analysis was performed to evaluate the association with susceptibility to AMD. These analyses reported that the SNPs rs11671784 (MIR27A, G/A) and rs2910164 (MIR146A, C/G) were significantly associated with AMD risk. Interestingly, the bioinformatic analysis showed that MIR27A and MIR146A take part in the angiogenic and inflammatory pathways underlying AMD etiopathogenesis. Thus, polymorphisms within the pre-miRNA sequences are likely to affect their functional activity, especially the interaction with specific targets. Therefore, our study represents a step forward in the comprehension of the mechanisms leading to AMD onset and progression, which certainly include the involvement of epigenetic modifications. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD))

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14 pages, 2063 KiB

Open AccessReview

Therapeutic Approaches with Intravitreal Injections in Geographic Atrophy Secondary to Age-Related Macular Degeneration: Current Drugs and Potential Molecules

by Marcella Nebbioso, Alessandro Lambiase, Alberto Cerini, Paolo Giuseppe Limoli, Maurizio La Cava and Antonio Greco

Int. J. Mol. Sci. 2019, 20(7), 1693; https://doi.org/10.3390/ijms20071693 - 4 Apr 2019

Cited by 39 | Viewed by 6523

Abstract

The present review focuses on recent clinical trials that analyze the efficacy of intravitreal therapeutic agents for the treatment of dry age-related macular degeneration (AMD), such as neuroprotective drugs, and complement inhibitors, also called immunomodulatory or anti-inflammatory agents. A systematic literature search was performed to identify randomized controlled trials published prior to January 2019. Patients affected by dry AMD treated with intravitreal therapeutic agents were included. Changes in the correct visual acuity and reduction in geographic atrophy progression were evaluated. Several new drugs have shown promising results, including those targeting the complement cascade and neuroprotective agents. The potential action of the two groups of drugs is to block complement cascade upregulation of immunomodulating agents, and to prevent the degeneration and apoptosis of ganglion cells for the neuroprotectors, respectively. Our analysis indicates that finding treatments for dry AMD will require continued collaboration among researchers to identify additional molecular targets and to fully interrogate the utility of pluripotent stem cells for personalized therapy. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD))

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18 pages, 5550 KiB

Open AccessArticle

Protective Effects of Curcumin Ester Prodrug, Curcumin Diethyl Disuccinate against H₂O₂-Induced Oxidative Stress in Human Retinal Pigment Epithelial Cells: Potential Therapeutic Avenues for Age-Related Macular Degeneration

by Chawanphat Muangnoi, Umar Sharif, Pahweenvaj Ratnatilaka Na Bhuket, Pornchai Rojsitthisak and Luminita Paraoan

Int. J. Mol. Sci. 2019, 20(13), 3367; https://doi.org/10.3390/ijms20133367 - 9 Jul 2019

Cited by 37 | Viewed by 5015

Abstract

Oxidative stress-induced damage to the retinal pigmented epithelium (RPE), a specialised post-mitotic monolayer that maintains retinal homeostasis, contributes to the development of age-related macular degeneration (AMD). Curcumin (Cur), a naturally occurring antioxidant, was previously shown to have the ability to protect RPE cells from oxidative stress. However, poor solubility and bioavailability makes Cur a poor therapeutic agent. As prodrug approaches can mitigate these limitations, we compared the protective properties of the Cur prodrug curcumin diethyl disuccinate (CurDD) against Cur in relation to oxidative stress induced in human ARPE-19 cells. Both CurDD and Cur significantly decreased H₂O₂-induced reactive oxygen species (ROS) production and protected RPE cells from oxidative stress-induced death. Both drugs exerted their protective effects through the modulation of p44/42 (ERK) and the involvement of downstream molecules Bax and Bcl-2. Additionally, the expression of antioxidant enzymes HO-1 and NQO1 was also enhanced in cells treated with CurDD and Cur. In all cases, CurDD was more effective than its parent drug against oxidative stress-induced damage to ARPE-19 cells. These findings highlight CurDD as a more potent drug compared to Cur against oxidative stress and indicate that its protective effects are exerted through modulation of key apoptotic and antioxidant molecular pathways. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD))

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19 pages, 5844 KiB

Open AccessReview

The Cytoskeleton of the Retinal Pigment Epithelium: from Normal Aging to Age-Related Macular Degeneration

by Ioana-Sandra Tarau, Andreas Berlin, Christine A. Curcio and Thomas Ach

Int. J. Mol. Sci. 2019, 20(14), 3578; https://doi.org/10.3390/ijms20143578 - 22 Jul 2019

Cited by 52 | Viewed by 9352

Abstract

The retinal pigment epithelium (RPE) is a unique epithelium, with major roles which are essential in the visual cycle and homeostasis of the outer retina. The RPE is a monolayer of polygonal and pigmented cells strategically placed between the neuroretina and Bruch membrane, adjacent to the fenestrated capillaries of the choriocapillaris. It shows strong apical (towards photoreceptors) to basal/basolateral (towards Bruch membrane) polarization. Multiple functions are bound to a complex structure of highly organized and polarized intracellular components: the cytoskeleton. A strong connection between the intracellular cytoskeleton and extracellular matrix is indispensable to maintaining the function of the RPE and thus, the photoreceptors. Impairments of these intracellular structures and the regular architecture they maintain often result in a disrupted cytoskeleton, which can be found in many retinal diseases, including age-related macular degeneration (AMD). This review article will give an overview of current knowledge on the molecules and proteins involved in cytoskeleton formation in cells, including RPE and how the cytoskeleton is affected under stress conditions—especially in AMD. Full article

(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD))

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