International Journal of Molecular Sciences

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 6415

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 [...] Read more.

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))

► Show Figures

Graphical abstract

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 72 | Viewed by 7357

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 [...] Read more.

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))

► Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
Metabolic and redox signaling regulated by the nucleoredoxin-like 1 gene products. 6PG: 6-phosphogluconate, BSG1: basigin-1, DHAP: dihydroxyacetone phosphate, F16BP: fructose-1,6-biphosphate, GLUT1: glucose transporter SLC2A1, G3P: Glycerol-3-phsopahe, G6P: glucose-6-phospate, G3PDH: glycerol-3-phosphate dehydrogenase, GAPDH: glyreraldeheyde-3-phosphate dehydrogenase, HK: hexokinase, LACT: lactate, LDHA: lactate dehydrogenase A, LDHAB: lactate dehydrogenase B, MPC: mitochondrial pyruvate carrier, NADPH: nicotinamide adenine dinucleotide phosphate, NXNL1: nucleoredoxin-like 1, PEP: phosphoenol pyruvate, PK: pyruvate kinase, PYR: pyruvate, PFK: phosphofructokinase, RdCVF: rod-derived cone viability factor (trophic factor), RdCVFL (thioredoxin enzyme), Ri5P: ribulose-5-phsophate, ROS: reactive oxygen species, SLC16A8: lactate transporter MCT3, TCA: tricarboxylic acid cycle, TPI: triosephosphate isomerase, TXNRD: thioredoxin reductase, red: reduced, ox: oxidized. Full article ">Figure 2
Metabolic reprogramming of inflammatory macrophages. Ac.CoA: acetyl-coenzyme A ACO2: aconitase mitochondrial, ASL: argininosuccinate lyase, ASS1: argininosuccinate synthase 1, CAD: cis-aconitate decarboxylase, Cis-Aco.: cis-aconitate, Cit.: citrate, Citru.: citrulline, DHAP: dihydroxyacetone phosphate, Fatty A.: fatty acids, FAS; Fatty acid synthase, G3P: Glycerol-3-phsopahe, G3PDH: glycerol-3-phosphate dehydrogenase, G6P: glucose-6-phospate, GLUT1: glucose transporter SLC2A1, HIF1A: hypoxia-inducible factor 1, IDH3: isocitrate dehydrogenase 3, IL1B: interleukine-1β, IRG1: immune-responsive gene 1, LACT: lactate, LDHA: lactate dehydrogenase A, MPC: mitochondrial pyruvate carrier, NADPH: nicotinamide adenine dinucleotide phosphate, NO: nitric oxide, NOS2: inducible nitric oxide synthase, NOX: NADPH oxidase, PFK: phosphofructokinase, PHD: prolyl-hydroxylase, PK: pyruvate kinase PYR: pyruvate, R: arginine, ROS: reactive oxygen species, SDH: succinate dehydrogenase, Suc.: succinate, SLC7A2: arginine transporter, SLC16A3, lactate transporter MCT4, SLC25A10: mitochondrial dicarboxylate carrier, TCA: tricarboxylic acid cycle, TPI: triosephosphate isomerase, VEGF: vascular endothelial growth factor. Full article ">Figure 3
Blood-derived inflammatory macrophage perturbation of the metabolic ecosystem between photoreceptors and the retinal pigmented epithelium. In non-pathological conditions, the rod on the left produces and secretes the truncated thioredoxin rod-derived cone viability factor (RdCVF, pink arrow toward the right). The cone on the right expresses the RdCVF cell-surface receptor basigin-1 (BSG1). RdCVF activates the complex formed between BSG1 and the glucose transporter GLUT1 (SLC2A1) resulting in an acceleration of the entry of glucose coming from the blood circulation through the retinal pigmented epithelium (RPE, on the top). The cone metabolizes glucose through aerobic glycolysis that produces glycerol-3-phosphate as a precursor of the hydrophilic head of the phospholipids (dark pink) for the renewal of the cone outer segment that contains the light-sensing molecule, the opsin (yellow). Aerobic glycolysis also produces lactate that is transported outside the cone by a lactate (lac) transporter. The lactate is partially transported through the RPE toward the blood circulation via two lactate transporters; the one on the basal side (on the top) is encoded by the SLC16A8 gene that carries risk alleles for AMD. A certain proportion of the transported lactate is metabolized by the RPE to pyruvate that fuels the mitochondrial oxidative phosphorylation. In that ecosystem, the glucose issued from the blood circulation is not metabolized by the RPE. In pathological conditions, as in patients carrying SLC16A8 risk alleles for AMD, the accumulation of lactate and its metabolism by the mitochondrial respiratory chain produces an excess of reactive oxygen species by leakage, and since lactate transporters are facilitating transporters, the rise in lactate in the RPE triggers an elevation of lactate in the extracellular space between photoreceptors. For the same mechanistic reason, an excess of lactate outside the cone counteracts the intracellular glycolytic flux and inhibits aerobic glycolysis, resulting in the shortening of the cone outer segment and the impairment of cone vision of the macula. This AMD pathological mechanism, identified through genome-wide association studies, may represent a genetic signature of a role of lactate produced after the metabolism reprogramming of inflammatory macrophages occurring in the disease due to chronic inflammation. This is illustrated by the infiltrated inflammatory macrophage (black, on the far right) which produces lactate and elevates the concentration of lactate in the retina, as does the SLC16A8 risk alleles. Full article ">

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 3387

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 [...] Read more.

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))

► Show Figures

Graphical abstract

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 19 | Viewed by 4931

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 [...] Read more.

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))

► Show Figures

Graphical abstract

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 4915

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 [...] Read more.

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))

► Show Figures

Graphical abstract

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 5414

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 [...] Read more.

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))

► Show Figures

Figure 1

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 10230

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 [...] Read more.

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))

► Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
Domain structure of the PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) protein. Numbers represent amino acid positions. L1-L3—leucine-rich domains, SR—serine and arginine-rich domains. PGC-1α interacts with transcription factors in a domain-specific fashion (horizontal lines above) and is post-translationally phosphorylated (P), acetylated (Ac), methylated (Me), and ubiquitinated (Ub) (mostly below). GNC5 acetylates and SIRT1 deacetylates PGC-1α. Full names of proteins interacting with PGC-1α are in the main text. Full article ">Figure 2
PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1α) is a master regulator of mitochondrial quality control (mtQC) during stress. Increased concentration of reactive oxygen species (ROS) results in damage to mitochondria. Damaged mitochondria are sensed by the joint action of PINK1 and Parkin. Dynamin related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1) are involved in dissection of damaged mitochondria (fission) into fragments, which can be ubiquitinated and degraded (autophagy, mitophagy), with the involvement of microtubule-associated protein 1A/1B-light chain 3 (LC3), or repaired (edited) and included into dynamic mitochondrial network (fusion) with the involvement of mitofusin 1 and 2 (MNF1/2). However, damaged mitochondria may accelerate ROS production, which activates pathways to prevent detrimental consequences of oxidative stress. Increased ROS activate AMPK (5′ AMP-activated protein kinase), which phosphorylates PGC-1α and increases NAD+ (nicotinamide adenine dinucleotide) concentration, leading to the activation of SIRT1 (Sirtuin 1). Concerted action of AMPK and SIRT1 results in PGC-1α phosphorylation and deacetylation, respectively, necessary for its activation. PGC-1α transactivates many genes encoding proteins essential in mitochondrial biogenesis, such as TFAM (mitochondrial transcription factor A), NRF-1 and 2 (nuclear respiratory factor 1 and 2), ERRs (estrogen-related receptors), and others (···). In mitophagy, AMPK inactivates mTOR (mammalian target of rapamycin), which inhibits ULK1 and 2 (Unc-51 like autophagy activating kinase 1 and 2). Mitochondria, through fission and fusion, are also able to repair damaged components by segregating or exchanging material (editing process). Full article ">Figure 3
Senescence may significantly contribute to the pathogenesis of age-related macular degeneration (AMD). Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) can decrease AMD-related detrimental changes. Retinal pigment epithelium (RPE) cells in the aging retina are continuously exposed to many environmental and lifestyle stress factors that accelerate aging and damage of RPE cells, leading to their senescence and lack of ability to regenerate their damaged and degenerated counterparts. Overproduction of ROS is an important element in this pathway as it is coupled with impaired DNA damage reaction (DDR) and dysfunctional autophagy, important elements of AMD pathogenesis, also contributing to senescence of RPE cells, which show senescence-associated secretory phenotype (SASP) and senescence-associated mitochondrial dysfunction (SAMD). Damage to RPE cells leads to degradation of organelles, including mitochondria, via mTOR (mechanistic target for rapamycin kinase)-dependent autophagy/mitophagy. PGC-1α can decrease ROS levels and protect against ROS-induced effects, including disrupted mitochondrial biogenesis. Full article ">Figure 4
PGC-1α is a negative regulator of senescence in RPE cells. Oxidative stress underlined by an ROS excess leads to stress-induced premature senescence (SIPS), characterized by increased expression of SA-β-gal, p53, p21, p16, which can be modulated by PGC-1α. SIPS is also associated with mitochondrial dysfunction, which can be improved by PGC-1α and telomere shortening, inducing DNA damage response with a major involvement of p53, stimulated by PGC-1α. Increased expression of SIRT1 induces deacetylation of FOXO1 and PGC-1α, resulting in senescence attenuation. Full names of proteins are in the main text. Full article ">Figure 5
Phagocytosis of photoreceptor outer segments (POS) in RPE cells can contribute to the protective action of PGC-1α against AMD. POS are internalized by RPE cells with the involvement of CD36 and MerTK, initiating their degradation by the autophagic/lysosomal pathway. Non-degraded POS and other material accumulate as lipofuscin, contributing to senescence. However, low levels of POS can protect RPE cells from senescence, and lack of POS phagocytosis results in accelerated age-related retinal dysfunctions. RPE cells bind POS by the activation of the avb5 αvβ5 integrin/FAK (focal adhesion kinase)/PGC-1α pathway. Full names of proteins are in the main text. Full article ">Figure 6
PGC-1α influences chronic inflammation associated with AMD. Degenerative changes in RPE cells observed in AMD and age-related changes in the immune system induce activation of the NLRP3 inflammasome and chronic inflammation in RPE cells. Inflammation affects mitochondria and induces their biogenesis, which is stimulated by PGC-1α with the involvement of many factors, including NRF-1 and Nfe212. Impaired mitochondria release mtDNA in cytosol, inducing NF-κB, a complex controlling inflammation, whose activity is inhibited by PGC-1α. Full names of proteins are in the main text. Full article ">Figure 7
Possible involvement of PGC-1α in AMD pathogenesis. Oxidative stress, resulting in ROS overproduction, evokes stress-induced premature senescence (SIPS) in aging RPE cells, leading to their degeneration and death observed in AMD. PGC-1α negatively regulates oxidative stress and senescence. SIPS and ROS excess result in disruption of mitochondria, inducing mechanisms of mitochondrial quality control (mtQC) and mitochondrial biogenesis with the involvement of PGC-1α. Mitophagy/autophagy seems to be especially important in that context. Processing of photoreceptor outer segments (POS) with involvement of PGC-1α and modulation of inflammation by this protein are other mechanisms of its protective action against AMD. Stimulation with intense light enhanced POS phagocytosis by RPE cells, which induced the activation of the PGC-1α/ERRα pathway, which in turn upregulated VEGF. Full article ">

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 50 | Viewed by 9189

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, [...] Read more.

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))

► Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
The cytoskeleton of the retinal pigment epithelium (RPE). (A) A cross-sectional view of the RPE and the adjacent photoreceptor outer segments (apical) and Bruch membrane (basal) highlights the intracellular network of cytoskeleton proteins: actin filaments, microtubules, and intermediate filaments. (B) The graph plots the dimension and protein structure of the above-mentioned cytoskeleton members: microfilaments consist of helical arranged polymers of actin proteins with an ATP-rich assembling (+)-end and a less energetic, ADP-rich disassembling (-)-end. Microtubules are hollow cylinders of tubulin proteins, also possessing an energetic, GTP-rich assembling (+)-end and a less energetic GDP-rich disassembling (-)-end. Intermediate filaments form rope-like fibers consisting of a large group of filament-organizing proteins. The regulating and associated proteins of each of the cytoskeleton substructures as mentioned in this review are listed (for details and additional regulating proteins, see detailed reviews from Bonilha and Hohmann et al. [<a href="#B32-ijms-20-03578" class="html-bibr">32</a>,<a href="#B33-ijms-20-03578" class="html-bibr">33</a>]). <a href="#ijms-20-03578-f001" class="html-fig">Figure 1</a>A: a reprint with permission from Elsevier (via RightsLink) and Vera Bonilha, PhD, and the Cleveland Clinic Center for Medical Art & Photography [<a href="#B32-ijms-20-03578" class="html-bibr">32</a>]. Full article ">Figure 2
Age-related differences in the RPE cytoskeleton in normal eyes. In young humans (36, 41 years), a uniform geometry of polygonal, mostly hexagonal RPE cells is present, both at the fovea and near periphery. At older ages (83, 90 years) the strict geometry loosens and shows some enlarged cells. This leads to an altered arrangement of the RPE cells. However, orderly packing and a stringent geometry can still be recognized, even at an advanced age. Despite these subtle changes in geometry, the total number of RPE cells at the posterior pole remains stable [<a href="#B22-ijms-20-03578" class="html-bibr">22</a>,<a href="#B141-ijms-20-03578" class="html-bibr">141</a>,<a href="#B142-ijms-20-03578" class="html-bibr">142</a>]. The use of human tissue has previously been approved by the Institutional Review Board at University of Alabama at Birmingham, AL, USA (Protocol X900525013; September 11, 2012. Full article ">Figure 3
RPE cytoskeleton alterations in age-related macular degeneration (AMD). In contrast to the normal architecture and to age-related changes in RPE geometry (<a href="#ijms-20-03578-f001" class="html-fig">Figure 1</a>), patchy areas with loss of the cells’ regular polygonal geometry and shape arise at AMD lesions (A,B). Prima facie, especially enlarged cells with a partly roundish shape (turquoise arrowheads) and variable irregular phenotypes are present. The ‘railroad tracks’-like arrangement of adjacent cells´ cytoskeleton bands is altered, showing separation (white arrowheads) and fragmentation or interruption (pink arrowheads). A special separation is sporadically seen: a splitting of the cytoskeleton (yellow arrowheads), which starts as small roundish lesions which then enlarge and finally might lead to a complete separation of two cells. A common finding in altered RPE cells is the presence of intracellular stress fibers (in B, blue arrowheads). At the insertion sites of the stress fibers, the actin filament cytoskeleton appears frayed and thickened (blue arrow). Donor: 83 years, female. RPE cells from the parafovea. F-actin labeled with AlexaFluor647-Phalloidin. Scale bar: 50 µm. Full article ">Figure 4
Cytoskeleton changes in AMD-affected eyes. In AMD, RPE cells and the cytoskeleton undergo significant changes. Drawings and photomicrographs show different cells with similar characteristics. (A) The loss of the cytoskeletons’ regular polygonal geometry and shape: enlarged cells with partly roundish cell shape and very variable cell sizes. (B) The separation of adjacent cells’ cytoskeleton bands. (C) The focal splitting of the cytoskeleton of two adjacent cells. These alterations are tiny in the beginning, but progress over time and can lead to a complete separation of two RPE cells. (D) Cytoskeleton fragmentation with dislocated free ends. Noticeably, the cell shape of these cells appears to be only minimally affected. (E) Enlarged RPE cells with a partly or complete thinned F-actin. (F) A thickened and frayed F-Actin. (G) In affected RPE cells, multiple intracellular stress fibers may appear. At sites where stress fibers insert, the cytoskeleton also appears frayed and thickened. Scale bar: 20 µm. Full article ">

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 10842

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 [...] Read more.

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))

► Show Figures

Figure 1

Figure 1
Schematic representation of the pathogenesis of age-related macular degeneration (AMD) with an important role of cellular waste (yellow highlight). Oxidative stress (red thunder) can be generated by many environmental/life style risk factors as well as yet unidentified sources. Visual cycle (VA) by-products can contribute to cellular waste. A complex interplay between oxidative stress, chronic inflammation, variants of genes encoding the complement and cellular waste clearing may lead to degeneration of retinal cells and clinically detectable AMD, which in its advanced stage may acquire the form of geographic atrophy (GA) or wet AMD, characterized by choroidal neovascularization (CNV). AMD symptoms include loss of central vision. Sharp black arrows indicate stimulation/consequences, whereas blunt black arrows—inhibition. PR—photoreceptors, RPE—retinal pigment epithelium, BM—Bruch’s membrane, Ch—choriocapillaris. Full article ">Figure 2
The visual cycle produces all-trans-retinal (atRAL), which is a major cellular waste in retinal cells. Light is absorbed by photoreceptors (PR) and causes isomerization of 11-cis-retinal to atRAL, which is transported and reduced to all-trans-retinol by ATP-binding transporter (ABCA4) and all trans retinal dehydrogenases RDH8/12, respectively. atRAL moves into retinal pigment epithelium (RPE), where it is converted to all-trans-retinyl esters by lecithin retinol acyltransferase (LRAT). RPE-specific protein (RPE65) isomerized these esters to 11-cis-retinol, which is then oxidized by RDH5 to 11-cis-retinal. Black arrows indicate a way from a compound to its derivative. Full article ">Figure 3
Fundus autofluorescence image from a degenerated macula indicating increased lipofuscin accumulation with increased autofluorescence signal. Full article ">Figure 4
Drusen are extracellular waste located between retinal pigment epithelium (RPE) cells and Bruch’s membrane (BM), which can disturb forward vision. They are clearly visible in fundus fluorescence as scattered light stains. PR—photoreceptors. Full article ">Figure 5
Cellular and extracellular waste clearing. Cellular waste, including misfolded, aggregated and damaged proteins as well as damaged organelles (presented as small ovals or squares of different colors) is subjected by two main machineries: ubiquitin-proteasome system (UPS) and autophagy, which can be in the form of macroautophagy, including mitophagy, microautophagy and chaperone-mediated autophagy (CMA). Unfolded proteins are a substrate for unfolded protein response (UPR, not represented here), which directs them to degradation either by autophagy or UPS. Heterophagy, which degrades extracellular debris inside the cell, is of a particular importance in retinal pigment epithelium cells and is usually carried out by endocytosis. Exosomes can transport waste material out of the cell. LAMP-2A—lysosomal associated membrane protein 2A. The black arrows indicate the sequence of events. Full article ">Figure 6
Unfolded protein response. When unfolded, misfolded and damaged proteins accumulate in endoplasmic reticulum (ER), they can induce unfolded protein response (UPR), a signaling cascade with the involvement of protein kinase-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). This cascade leads to a stop in translation of faulty proteins, degradation of misfolded proteins and increased synthesis of chaperons involved in protein folding. If these mechanisms fall, UPR switch to pro-apoptotic response. XBP1s—X-box binding protein 1 specificity protein, eIF2—translation initiation factor 2, ERAD—ER-associated degradation, ATF6f—the transcriptional activator domain of ATF6, P—phosphate residue. Full article ">Figure 7
EI24 (etoposide-induced protein 2.4 homolog) is the main connection between ubiquitin-mediated proteasomal system (UPS) and autophagy. The concerted action of ubiquitin ligases E1-E3 results in ubiquitination of target proteins to label for UPS-mediated degradation. Ubiquitin chain transfer to target proteins is catalyzed by the RING-domain E3 ligases. EI24, an autophagy-inducing protein, can cause autophagy-mediated degradation of RING-domain E3 ligases. Thick arrows represent main pathways, thin arrows—side pathways. Full article ">

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 49 | Viewed by 8627

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, [...] Read more.

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))

► Show Figures

Figure 1

Figure 1
Schematic representation summarizing the transforming growth factors-beta (TGF-β) receptor complexes and signaling pathway in endothelial cells. The green arrowhead lines represent positive crosstalk interactions and steps. Red flat-ended lines indicate inhibition. In the nucleus, the green arrowhead and red flat-ended lines on the DNA represent activation and inhibition of gene expression, respectively. (a) LAP-TGF-β latent complex. (b) Release of TGF-β from the complex with LAP. (c) TGF-β binding to the heterotetrameric receptor complex. (d) TβRII phosphorylation of type I receptor ALK5. (e) SMAD2/3 phosphorylation by ALK5. (f) SMAD1/5/8 phosphorylation by ALK1. (g) Dimerization of R-SMADs with SMAD4. (h) Translocation of the R-SMAD/SMAD4 complex into the nucleus and binding to regulatory sequences. See text for details. Full article ">Figure 2
Drawing of a section through the human eye with a schematic enlargement of the retina layers. The TGF-β1 (a), TGF-β2 (b) and TGF-β3 (c) expression in human eye structures and cells are indicated by different colors. See text for details. Full article ">Figure 3
Schematic representation summarizing the evidence of a proangiogenic (left column) and antiangiogenic (right column) role played by TGF-β in nAMD. Arrows pointing up indicate upregulation, and arrows pointing down indicate downregulation. Red and blue lines connect each experimental evidence with the related site in the eye. Where not specified, the experimental procedures adopted do not permit one to unequivocally identify the TGF-β type involved. EC: endothelial cells; EMT: epithelial-to-mesenchymal transition; CNV: choroidal neovascularization; LI-CNV: laser-induced CNV; RPE: retinal pigment epithelium. See text for details. Full article ">

Journal Menu

Journal Browser

Molecular Biology of Age-Related Macular Degeneration (AMD)

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Related Special Issue

Published Papers (10 papers)

Further Information

Guidelines

MDPI Initiatives

Follow MDPI