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Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0
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Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0

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

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 92633

Special Issue Editors

Prof. Dr. Janusz Blasiak

E-Mail Website
Guest Editor
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
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Kai Kaarniranta

E-Mail Website
Co-Guest Editor
Department of Ophthalmology, Kuopio University Hospital, 70211 Kuopio, Finland
Interests: aging; autophagy; eye diseases; genetics; macula; oxidative stress; proteolysis; retinal pigment epithelium
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

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 is associated 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 abovementioned issues, or of the topics mentioned in the keywords listed below.

This Special Issue is the continuation of our previous Special Issue, “Molecular Biology of Age-Related Macular Degeneration (AMD)”.

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

Manuscript Submission Information

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

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

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

Keywords

  • 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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Published Papers (18 papers)

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22 pages, 5683 KiB  
Article
Targeting Lysosomes to Reverse Hydroquinone-Induced Autophagy Defects and Oxidative Damage in Human Retinal Pigment Epithelial Cells
by Samuel Abokyi, Sze-Wan Shan, Christie Hang-I Lam, Kirk Patrick Catral, Feng Pan, Henry Ho-Lung Chan, Chi-Ho To and Dennis Yan-Yin Tse
Int. J. Mol. Sci. 2021, 22(16), 9042; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22169042 - 22 Aug 2021
Cited by 8 | Viewed by 3477
Abstract
In age-related macular degeneration (AMD), hydroquinone (HQ)-induced oxidative damage in retinal pigment epithelium (RPE) is believed to be an early event contributing to dysregulation of inflammatory cytokines and vascular endothelial growth factor (VEGF) homeostasis. However, the roles of antioxidant mechanisms, such as autophagy [...] Read more.
In age-related macular degeneration (AMD), hydroquinone (HQ)-induced oxidative damage in retinal pigment epithelium (RPE) is believed to be an early event contributing to dysregulation of inflammatory cytokines and vascular endothelial growth factor (VEGF) homeostasis. However, the roles of antioxidant mechanisms, such as autophagy and the ubiquitin-proteasome system, in modulating HQ-induced oxidative damage in RPE is not well-understood. This study utilized an in-vitro AMD model involving the incubation of human RPE cells (ARPE-19) with HQ. In comparison to hydrogen peroxide (H2O2), HQ induced fewer reactive oxygen species (ROS) but more oxidative damage as characterized by protein carbonyl levels, mitochondrial dysfunction, and the loss of cell viability. HQ blocked the autophagy flux and increased proteasome activity, whereas H2O2 did the opposite. Moreover, the lysosomal membrane-stabilizing protein LAMP2 and cathepsin D levels declined with HQ exposure, suggesting loss of lysosomal membrane integrity and function. Accordingly, HQ induced lysosomal alkalization, thereby compromising the acidic pH needed for optimal lysosomal degradation. Pretreatment with MG132, a proteasome inhibitor and lysosomal stabilizer, upregulated LAMP2 and autophagy and prevented HQ-induced oxidative damage in wildtype RPE cells but not cells transfected with shRNA against ATG5. This study demonstrated that lysosomal dysfunction underlies autophagy defects and oxidative damage induced by HQ in human RPE cells and supports lysosomal stabilization with the proteasome inhibitor MG132 as a potential remedy for oxidative damage in RPE and AMD. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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18 pages, 1587 KiB  
Article
CFH Loss in Human RPE Cells Leads to Inflammation and Complement System Dysregulation via the NF-κB Pathway
by Angela Armento, Tiziana L. Schmidt, Inga Sonntag, David A. Merle, Mohamed Ali Jarboui, Ellen Kilger, Simon J. Clark and Marius Ueffing
Int. J. Mol. Sci. 2021, 22(16), 8727; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168727 - 13 Aug 2021
Cited by 17 | Viewed by 3124
Abstract
Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease, and chronic inflammatory processes may be involved. Besides [...] Read more.
Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease, and chronic inflammatory processes may be involved. Besides aging and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (CFH), accounting for the majority of AMD risk. However, the exact mechanism of CFH dysregulation confers such a great risk for AMD and its role in RPE cell homeostasis is unclear. To explore the role of endogenous CFH locally in RPE cells, we silenced CFH in human hTERT-RPE1 cells. We demonstrate that endogenously expressed CFH in RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources, or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g., IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g., C3, CFB upregulation, and C5 downregulation) that are known to play a role in AMD. Moreover, our results identify the NF-κB pathway as the major pathway involved in regulating these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-κB pathway work in synergy to maintain inflammatory and complement balance, and in case either one of them is dysregulated, the RPE microenvironment changes towards a proinflammatory AMD-like phenotype. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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17 pages, 3901 KiB  
Article
Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice
by Janusz Blasiak, Ali Koskela, Elzbieta Pawlowska, Mikko Liukkonen, Johanna Ruuth, Elisa Toropainen, Juha M. T. Hyttinen, Johanna Viiri, John E. Eriksson, Heping Xu, Mei Chen, Szabolcs Felszeghy and Kai Kaarniranta
Int. J. Mol. Sci. 2021, 22(4), 1684; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041684 - 08 Feb 2021
Cited by 13 | Viewed by 3583
Abstract
Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness worldwide in the elderly population. In our previous studies, we found that deficiencies in the nuclear factor, erythroid 2 like 2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator 1-α [...] Read more.
Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness worldwide in the elderly population. In our previous studies, we found that deficiencies in the nuclear factor, erythroid 2 like 2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) genes caused AMD-like pathological phenotypes in mice. In the present work, we show hijacked epithelial-mesenchymal transition (EMT) due to the common loss of PGC-1α and NFE2L2 (double knock-out, dKO) genes in aged animals. The implanted area was assessed by histology, immunohistochemistry and transmission electron microscopy. Confocal microscopy revealed altered regions in the filamentous actin ring. This contrasted with hexagonal RPE morphology in wild-type mice. The ultrastructural RPE features here illustrated loss of apical microvilli, alteration of cell-cell contact, loss of basal in-folding with deposits on Bruch’s membrane, and excessive lipofuscin deposition in dKO samples. We also found the expression of epithelial-mesenchymal transition transcription factors, such as Snail, Slug, collagen 1, vimentin and OB-cadherin, to be significantly different in dKO RPEs. An increased immunoreactivity of senescence markers p16, DEC1 and HMGB1 was also noted. These findings suggest that EMT and senescence pathways may intersect in the retinas of dKO mice. Both processes can be activated by damage to the RPE, which may be caused by increased oxidative stress resulting from the absence of NFE2L2 and PGC-1α genes, important for antioxidant defense. This dKO model may provide useful tools for studying AMD pathogenesis and evaluating novel therapies for this disease. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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16 pages, 2041 KiB  
Communication
3D-Reconstructed Retinal Pigment Epithelial Cells Provide Insights into the Anatomy of the Outer Retina
by Eloise Keeling, David S. Chatelet, Nicole Y. T. Tan, Farihah Khan, Rhys Richards, Thibana Thisainathan, Patricia Goggin, Anton Page, David A. Tumbarello, Andrew J. Lotery and J. Arjuna Ratnayaka
Int. J. Mol. Sci. 2020, 21(21), 8408; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218408 - 09 Nov 2020
Cited by 13 | Viewed by 5149
Abstract
The retinal pigment epithelium (RPE) is located between the neuroretina and the choroid, and plays a critical role in vision. RPE cells internalise outer segments (OS) from overlying photoreceptors in the daily photoreceptor renewal. Changes to RPE structure are linked with age and [...] Read more.
The retinal pigment epithelium (RPE) is located between the neuroretina and the choroid, and plays a critical role in vision. RPE cells internalise outer segments (OS) from overlying photoreceptors in the daily photoreceptor renewal. Changes to RPE structure are linked with age and retinopathy, which has been described in the past by conventional 2D electron microscopy. We used serial block face scanning electron microscopy (SBF-SEM) to reconstruct RPE cells from the central mouse retina. Three-dimensional-reconstructed OS revealed the RPE to support large numbers of photoreceptors (90–216 per RPE cell). Larger bi-nucleate RPE maintained more photoreceptors, although their cytoplasmic volume was comparable to smaller mono-nucleate RPE supporting fewer photoreceptors. Scrutiny of RPE microvilli and interdigitating OS revealed the angle and surface area of contact between RPE and photoreceptors. Bi-nucleate RPE contained more mitochondria compared to mono-nucleate RPE. Furthermore, bi-nucleate cells contained larger sub-RPE spaces, supporting a likely association with disease. Use of perfusion-fixed tissues ensured the highest possible standard of preservation, providing novel insights into the 3D RPE architecture and changes linked with retinopathy. This study serves as a benchmark for comparing retinal tissues from donor eyes with age-related macular degeneration (AMD) and other retinopathies. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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23 pages, 5284 KiB  
Article
An In-Vitro Cell Model of Intracellular Protein Aggregation Provides Insights into RPE Stress Associated with Retinopathy
by Eloise Keeling, Annabelle J. Culling, David A. Johnston, David S. Chatelet, Anton Page, David A. Tumbarello, Andrew J. Lotery and J. Arjuna Ratnayaka
Int. J. Mol. Sci. 2020, 21(18), 6647; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186647 - 11 Sep 2020
Cited by 6 | Viewed by 3332
Abstract
Impaired cargo trafficking and the aggregation of intracellular macromolecules are key features of neurodegeneration, and a hallmark of aged as well as diseased retinal pigment epithelial (RPE) cells in the eye. Here, photoreceptor outer segments (POS), which are internalized daily by RPE cells, [...] Read more.
Impaired cargo trafficking and the aggregation of intracellular macromolecules are key features of neurodegeneration, and a hallmark of aged as well as diseased retinal pigment epithelial (RPE) cells in the eye. Here, photoreceptor outer segments (POS), which are internalized daily by RPE cells, were modified by UV-irradiation to create oxidatively modified POS (OxPOS). Oxidative modification was quantified by a protein carbonyl content assay. Human ARPE-19 cells were synchronously pulsed with POS or OxPOS to study whether oxidatively modified cargos can recapitulate features of RPE pathology associated with blinding diseases. Confocal immunofluorescence microscopy analysis showed that OxPOS was trafficked to LAMP1, LAMP2 lysosomes and to LC3b autophagy vacuoles. Whilst POS were eventually degraded, OxPOS cargos were sequestered in late compartments. Co-localization of OxPOS was also associated with swollen autolysosomes. Ultrastructural analysis revealed the presence of electron-dense OxPOS aggregates in RPE cells, which appeared to be largely resistant to degradation. Measurement of cellular autofluorescence, using parameters used to assess fundus autofluorescence (FAF) in age-related macular disease (AMD) patients, revealed that OxPOS contributed significantly to a key feature of aged and diseased RPE. This in vitro cell model therefore represents a versatile tool to study disease pathways linked with RPE damage and sight-loss. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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16 pages, 1692 KiB  
Article
Alterations of STEP46 and STEP61 Expression in the Rat Retina with Age and AMD-Like Retinopathy Development
by Darya V. Telegina, Elizabeth A. Kulikova, Oyuna S. Kozhevnikova, Alexander V. Kulikov, Tatyana M. Khomenko, Konstantin P. Volcho, Nariman F. Salakhutdinov and Nataliya G. Kolosova
Int. J. Mol. Sci. 2020, 21(15), 5182; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155182 - 22 Jul 2020
Cited by 3 | Viewed by 2610
Abstract
Tyrosine phosphatase STEP (striatal-enriched tyrosine protein phosphatase) is a brain-specific protein phosphatase and is involved in the pathogenesis of many neurodegenerative diseases. Here, we examined the impact of STEP on the development of age-related macular degeneration (AMD)-like pathology in senescence-accelerated OXYS rats. Using [...] Read more.
Tyrosine phosphatase STEP (striatal-enriched tyrosine protein phosphatase) is a brain-specific protein phosphatase and is involved in the pathogenesis of many neurodegenerative diseases. Here, we examined the impact of STEP on the development of age-related macular degeneration (AMD)-like pathology in senescence-accelerated OXYS rats. Using OXYS and Wistar rats (control), we for the first time demonstrated age-dependent changes in Ptpn5 mRNA expression, STEP46 and STEP61 protein levels, and their phosphatase activity in the retina. The increases in STEP protein levels and the decrease of total and STEP phosphatase activities in the retina (as compared with Wistar rats) preceded the manifestation of clinical signs of AMD in OXYS rats (age 20 days). There were no differences in these retinal parameters between 13-month-old Wistar rats and OXYS rats with pronounced signs of AMD. Inhibition of STEP with TC-2153 during progressive AMD-like retinopathy (from 9 to 13 months of age) reduced the thickness of the retinal inner nuclear layer, as evidenced by a decreased amount of parvalbumin-positive amacrine neurons. Prolonged treatment with TC-2153 had no effect on Ptpn5 mRNA expression, STEP46 and STEP61 protein levels, and their phosphatase activity in the OXYS retina. Thus, TC-2153 may negatively affect the retina through mechanisms unrelated to STEP. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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19 pages, 4663 KiB  
Article
Effects of FTMT Expression by Retinal Pigment Epithelial Cells on Features of Angiogenesis
by Undral Buyandelger, Douglas G. Walker, Daijiro Yanagisawa, Toshifumi Morimura and Ikuo Tooyama
Int. J. Mol. Sci. 2020, 21(10), 3635; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103635 - 21 May 2020
Cited by 4 | Viewed by 3920
Abstract
Aberrant angiogenesis is a pathological feature of a number of diseases and arises from the uncoordinated expression of angiogenic factors as response to different cellular stresses. Age-related macular degeneration (AMD), a leading cause of vision loss, can result from pathological angiogenesis. As a [...] Read more.
Aberrant angiogenesis is a pathological feature of a number of diseases and arises from the uncoordinated expression of angiogenic factors as response to different cellular stresses. Age-related macular degeneration (AMD), a leading cause of vision loss, can result from pathological angiogenesis. As a mutation in the mitochondrial ferritin (FTMT) gene has been associated with AMD, its possible role in modulating angiogenic factors and angiogenesis was investigated. FTMT is an iron-sequestering protein primarily expressed in metabolically active cells and tissues with high oxygen demand, including retina. In this study, we utilized the human retinal pigment epithelial cell line ARPE-19, both as undifferentiated and differentiated cells. The effects of proinflammatory cytokines, FTMT knockdown, and transient and stable overexpression of FTMT were investigated on expression of pro-angiogenic vascular endothelial growth factor (VEGF) and anti-angiogenic pigment epithelial-derived factor (PEDF). Proinflammatory cytokines induced FTMT and VEGF expression, while NF-κB inhibition significantly reduced FTMT expression. VEGF protein and mRNA expression were significantly increased in FTMT-silenced ARPE-19 cells. Using an in vitro angiogenesis assay with endothelial cells, we showed that conditioned media from FTMT-overexpressing cells had significant antiangiogenic effects. Collectively, our findings indicate that increased levels of FTMT inhibit angiogenesis, possibly by reducing levels of VEGF and increasing PEDF expression. The cellular models developed can be used to investigate if increased FTMT may be protective in angiogenic diseases, such as AMD. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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13 pages, 2657 KiB  
Article
Resvega Alleviates Hydroquinone-Induced Oxidative Stress in ARPE-19 Cells
by Niina Bhattarai, Eveliina Korhonen, Maija Toppila, Ali Koskela, Kai Kaarniranta, Yashavanthi Mysore and Anu Kauppinen
Int. J. Mol. Sci. 2020, 21(6), 2066; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062066 - 17 Mar 2020
Cited by 17 | Viewed by 4564
Abstract
Retinal pigment epithelial (RPE) cells maintain homeostasis at the retina and they are under continuous oxidative stress. Cigarette smoke is a prominent environmental risk factor for age-related macular degeneration (AMD), which further increases the oxidant load in retinal tissues. In this study, we [...] Read more.
Retinal pigment epithelial (RPE) cells maintain homeostasis at the retina and they are under continuous oxidative stress. Cigarette smoke is a prominent environmental risk factor for age-related macular degeneration (AMD), which further increases the oxidant load in retinal tissues. In this study, we measured oxidative stress and inflammatory markers upon cigarette smoke-derived hydroquinone exposure on human ARPE-19 cells. In addition, we studied the effects of commercial Resvega product on hydroquinone-induced oxidative stress. Previously, it was observed that Resvega induces autophagy during impaired protein clearance in ARPE-19 cells, for which it has the potential to alleviate pro-inflammatory pathways. Cell viability was determined while using the lactate dehydrogenase (LDH) and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and the cytokine levels were measured using the enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) production were measured using the 2′,7′-dichlorofluorescin diacetate (H2DCFDA) probe. Hydroquinone compromised the cell viability and increased ROS production in ARPE-19 cells. Resvega significantly improved cell viability upon hydroquinone exposure and reduced the release of interleukin (IL)-8 and monocytic chemoattractant protein (MCP)-1 from RPE cells. Resvega, N-acetyl-cysteine (NAC) and aminopyrrolidine-2,4-dicarboxylic acid (APDC) alleviated hydroquinone-induced ROS production in RPE cells. Collectively, our results indicate that hydroquinone induces cytotoxicity and increases oxidative stress through NADPH oxidase activity in RPE cells, and resveratrol-containing Resvega products prevent those adverse effects. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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18 pages, 5434 KiB  
Article
Mitophagy in the Retinal Pigment Epithelium of Dry Age-Related Macular Degeneration Investigated in the NFE2L2/PGC-1α-/- Mouse Model
by Iswariyaraja Sridevi Gurubaran, Johanna Viiri, Ali Koskela, Juha M.T. Hyttinen, Jussi J. Paterno, Gréta Kis, Miklós Antal, Arto Urtti, Anu Kauppinen, Szabolcs Felszeghy and Kai Kaarniranta
Int. J. Mol. Sci. 2020, 21(6), 1976; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21061976 - 13 Mar 2020
Cited by 35 | Viewed by 5663
Abstract
Increased oxidative stress and mitochondrial damage are observed in protein aggregation diseases, such as age-related macular degeneration (AMD). We have recently reported elevated levels of oxidative stress markers, damaged mitochondria, accumulating lysosomal lipofuscin and extracellular drusen-like structures in the retinal pigment epithelial cells [...] Read more.
Increased oxidative stress and mitochondrial damage are observed in protein aggregation diseases, such as age-related macular degeneration (AMD). We have recently reported elevated levels of oxidative stress markers, damaged mitochondria, accumulating lysosomal lipofuscin and extracellular drusen-like structures in the retinal pigment epithelial cells (RPE) of the dry AMD-resembling NFE2L2/PGC1α double knockout (dKO) mouse model. Here, we provide evidence of a disturbance in the autolysosomal machinery handling mitochondrial clearance in the RPE cells of one-year-old NFE2L2/PGC1α-deficient mice. Confocal immunohistochemical analysis revealed an upregulation of autophagosome marker microtubule-associated proteins 1A/1B light chain 3B (LC3B) as well as numerous mitophagy markers, such as PTE-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase (PARKIN) together with damaged mitochondria. However, we detected no evidence of increased autolysosome formation in transmission electron micrographs or of colocalization of lysosomal marker LAMP2 (lysosome-associated membrane protein 2) and the mitochondrial marker ATP synthase β in confocal micrographs. Interestingly, we observed an upregulation of late autolysosomal fusion Ras-related protein (Rab7) in the perinuclear space of RPE cells together with autofluorescence aggregates. Our results reveal that there is at least a relative decrease of mitophagy in the RPE cells of NFE2L2/PGC1α dKO mice. This further supports the hypothesis that mitophagy is a putative therapy target in AMD-like pathology. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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12 pages, 4120 KiB  
Article
Resveratrol as Inducer of Autophagy, Pro-Survival, and Anti-Inflammatory Stimuli in Cultured Human RPE Cells
by Natasha Josifovska, Réka Albert, Richárd Nagymihály, Lyubomyr Lytvynchuk, Morten C. Moe, Kai Kaarniranta, Zoltán J. Veréb and Goran Petrovski
Int. J. Mol. Sci. 2020, 21(3), 813; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030813 - 27 Jan 2020
Cited by 36 | Viewed by 4628
Abstract
Purpose: To investigate the mechanism by which resveratrol acts upon retinal pigment epithelial (RPE) cells and to characterize its effect upon autophagy, survival, and inflammation, with consequent implications to treatment for age-related macular degeneration (AMD). Methods: Cultured ARPE-19 cells were exposed to 10 [...] Read more.
Purpose: To investigate the mechanism by which resveratrol acts upon retinal pigment epithelial (RPE) cells and to characterize its effect upon autophagy, survival, and inflammation, with consequent implications to treatment for age-related macular degeneration (AMD). Methods: Cultured ARPE-19 cells were exposed to 10 and 50 μM resveratrol. Cell survival/death was determined by annexin-FITC/propidium iodide using flow cytometry, while autophagy was studied by detecting autophagic vacuoles formation (acridine orange and transmission electron microscopy), as well as LC3II/I ratio and p62 expression by Western blot. In addition, time-lapse confocal microscopy of a pDENDRA-LC3 expression vector was performed to detect autophagy in transfected ARPE-19 cells under the different treatment conditions. Inhibition of proteasomal and autophagy-lysosomal fusion was carried out by MG-132 and chloroquine, respectively, while induction of autophagy was achieved by rapamycin treatment. Detection of secreted cytokines by ARPE-19 cells using Human XL Cytokine Array was performed under oxidative stress (H2O2) and resveratrol treatments, respectively. Results: Resveratrol induced autophagy in ARPE-19 cells as determined by augmented presence of autophagic vacuoles, increased LC3II/I ratio and decreased p62 expression, as well as time-lapse confocal microscopy using pDENDRA-LC3 expression vector. Resveratrol acted similarly to proteasomal inhibition and downstream of mammalian target of rapamycin (mTOR), since upstream inhibition of autophagy by 3-methyladenine could not inhibit autophagy in ARPE-19 cells. Co-treatmeant by rapamycin and/or proteasome inhibition showed no additive effect upon autophagy induction. ARPE-19 cells treated by resveratrol showed lower cell death rate compared to untreated controls. Resveratrol induced a specific anti-inflammatory response in ARPE-19 cells. Conclusions: Resveratrol can induce autophagy, pro-survival, and anti-inflammatory stimuli in ARPE-19 cells, properties which could be plausible to formulate future treatment modalities for AMD. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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13 pages, 4124 KiB  
Article
Lack of Delta-Sarcoglycan (Sgcd) Results in Retinal Degeneration
by Andric C. Perez-Ortiz, Martha J. Peralta-Ildefonso, Esmeralda Lira-Romero, Ernesto Moya-Albor, Jorge Brieva, Israel Ramirez-Sanchez, Carmen Clapp, Alexandra Luna-Angulo, Alvaro Rendon, Elva Adan-Castro, Gabriela Ramírez-Hernández, Nundehui Díaz-Lezama, Ramón M. Coral-Vázquez and Francisco J. Estrada-Mena
Int. J. Mol. Sci. 2019, 20(21), 5480; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215480 - 04 Nov 2019
Cited by 8 | Viewed by 3593
Abstract
Age-related macular degeneration (AMD) is the leading cause of central vision loss and severe blindness among the elderly population. Recently, we reported on the association of the SGCD gene (encoding for δ-sarcoglycan) polymorphisms with AMD. However, the functional consequence of Sgcd alterations in [...] Read more.
Age-related macular degeneration (AMD) is the leading cause of central vision loss and severe blindness among the elderly population. Recently, we reported on the association of the SGCD gene (encoding for δ-sarcoglycan) polymorphisms with AMD. However, the functional consequence of Sgcd alterations in retinal degeneration is not known. Herein, we characterized changes in the retina of the Sgcd knocked-out mouse (KO, Sgcd−/−). At baseline, we analyzed the retina structure of three-month-old wild-type (WT, Sgcd+/+) and Sgcd−/− mice by hematoxylin and eosin (H&E) staining, assessed the Sgcd–protein complex (α-, β-, γ-, and ε-sarcoglycan, and sarcospan) by immunofluorescence (IF) and Western blot (WB), and performed electroretinography. Compared to the WT, Sgcd−/− mice are five times more likely to have retinal ruptures. Additionally, all the retinal layers are significantly thinner, more so in the inner plexiform layer (IPL). In addition, the number of nuclei in the KO versus the WT is ever so slightly increased. WT mice express Sgcd-protein partners in specific retinal layers, and as expected, KO mice have decreased or no protein expression, with a significant increase in the α subunit. At three months of age, there were no significant differences in the scotopic electroretinographic responses, regarding both a- and b-waves. According to our data, Sgcd−/− has a phenotype that is compatible with retinal degeneration. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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Review

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18 pages, 1587 KiB  
Review
Features of Retinal Neurogenesis as a Key Factor of Age-Related Neurodegeneration: Myth or Reality?
by Darya V. Telegina, Oyuna S. Kozhevnikova, Anna K. Antonenko and Nataliya G. Kolosova
Int. J. Mol. Sci. 2021, 22(14), 7373; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147373 - 09 Jul 2021
Cited by 3 | Viewed by 2916
Abstract
Age-related macular degeneration (AMD) is a complex multifactorial neurodegenerative disease that constitutes the most common cause of irreversible blindness in the elderly in the developed countries. Incomplete knowledge about its pathogenesis prevents the search for effective methods of prevention and treatment of AMD, [...] Read more.
Age-related macular degeneration (AMD) is a complex multifactorial neurodegenerative disease that constitutes the most common cause of irreversible blindness in the elderly in the developed countries. Incomplete knowledge about its pathogenesis prevents the search for effective methods of prevention and treatment of AMD, primarily of its “dry” type which is by far the most common (90% of all AMD cases). In the recent years, AMD has become “younger”: late stages of the disease are now detected in relatively young people. It is known that AMD pathogenesis—according to the age-related structural and functional changes in the retina—is linked with inflammation, hypoxia, oxidative stress, mitochondrial dysfunction, and an impairment of neurotrophic support, but the mechanisms that trigger the conversion of normal age-related changes to the pathological process as well as the reason for early AMD development remain unclear. In the adult mammalian retina, de novo neurogenesis is very limited. Therefore, the structural and functional features that arise during its maturation and formation can exert long-term effects on further ontogenesis of this tissue. The aim of this review was to discuss possible contributions of the changes/disturbances in retinal neurogenesis to the early development of AMD. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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20 pages, 1579 KiB  
Review
Potential of Telomerase in Age-Related Macular Degeneration—Involvement of Senescence, DNA Damage Response and Autophagy and a Key Role of PGC-1α
by Janusz Blasiak, Joanna Szczepanska, Michal Fila, Elzbieta Pawlowska and Kai Kaarniranta
Int. J. Mol. Sci. 2021, 22(13), 7194; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137194 - 03 Jul 2021
Cited by 11 | Viewed by 4112
Abstract
Age-related macular degeneration (AMD), the main cause of vision loss in the elderly, is associated with oxidation in the retina cells promoting telomere attrition. Activation of telomerase was reported to improve macular functions in AMD patients. The catalytic subunit of human telomerase (hTERT) [...] Read more.
Age-related macular degeneration (AMD), the main cause of vision loss in the elderly, is associated with oxidation in the retina cells promoting telomere attrition. Activation of telomerase was reported to improve macular functions in AMD patients. The catalytic subunit of human telomerase (hTERT) may directly interact with proteins important for senescence, DNA damage response, and autophagy, which are impaired in AMD. hTERT interaction with mTORC1 (mTOR (mechanistic target of rapamycin) complex 1) and PINK1 (PTEN-induced kinase 1) activates macroautophagy and mitophagy, respectively, and removes cellular debris accumulated over AMD progression. Ectopic expression of telomerase in retinal pigment epithelium (RPE) cells lengthened telomeres, reduced senescence, and extended their lifespan. These effects provide evidence for the potential of telomerase in AMD therapy. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may be involved in AMD pathogenesis through decreasing oxidative stress and senescence, regulation of vascular endothelial growth factor (VEGF), and improving autophagy. PGC-1α and TERT form an inhibitory positive feedback loop. In conclusion, telomerase activation and its ectopic expression in RPE cells, as well as controlled clinical trials on the effects of telomerase activation in AMD patients, are justified and should be assisted by PGC-1α modulators to increase the therapeutic potential of telomerase in AMD. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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32 pages, 1886 KiB  
Review
Matrix Metalloproteinases in Age-Related Macular Degeneration (AMD)
by Luis García-Onrubia, Fco. Javier Valentín-Bravo, Rosa M. Coco-Martin, Rogelio González-Sarmiento, J. Carlos Pastor, Ricardo Usategui-Martín and Salvador Pastor-Idoate
Int. J. Mol. Sci. 2020, 21(16), 5934; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165934 - 18 Aug 2020
Cited by 31 | Viewed by 5225
Abstract
Age-related macular degeneration (AMD) is a complex, multifactorial and progressive retinal disease affecting millions of people worldwide. In developed countries, it is the leading cause of vision loss and legal blindness among the elderly. Although the pathogenesis of AMD is still barely understood, [...] Read more.
Age-related macular degeneration (AMD) is a complex, multifactorial and progressive retinal disease affecting millions of people worldwide. In developed countries, it is the leading cause of vision loss and legal blindness among the elderly. Although the pathogenesis of AMD is still barely understood, recent studies have reported that disorders in the regulation of the extracellular matrix (ECM) play an important role in its etiopathogenesis. The dynamic metabolism of the ECM is closely regulated by matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). The present review focuses on the crucial processes that occur at the level of the Bruch’s membrane, with special emphasis on MMPs, TIMPs, and the polymorphisms associated with increased susceptibility to AMD development. A systematic literature search was performed, covering the years 1990–2020, using the following keywords: AMD, extracellular matrix, Bruch’s membrane, MMPs, TIMPs, and MMPs polymorphisms in AMD. In both early and advanced AMD, the pathological dynamic changes of ECM structural components are caused by the dysfunction of specific regulators and by the influence of other regulatory systems connected with both genetic and environmental factors. Better insight into the pathological role of MMP/TIMP complexes may lead to the development of new strategies for AMD treatment and prevention. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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19 pages, 1722 KiB  
Review
Zinc and Autophagy in Age-Related Macular Degeneration
by Janusz Blasiak, Elzbieta Pawlowska, Jan Chojnacki, Joanna Szczepanska, Cezary Chojnacki and Kai Kaarniranta
Int. J. Mol. Sci. 2020, 21(14), 4994; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144994 - 15 Jul 2020
Cited by 19 | Viewed by 6718
Abstract
Zinc supplementation is reported to slow down the progression of age-related macular degeneration (AMD), but there is no general consensus on the beneficiary effect on zinc in AMD. As zinc can stimulate autophagy that is declined in AMD, it is rational to assume [...] Read more.
Zinc supplementation is reported to slow down the progression of age-related macular degeneration (AMD), but there is no general consensus on the beneficiary effect on zinc in AMD. As zinc can stimulate autophagy that is declined in AMD, it is rational to assume that it can slow down its progression. As melanosomes are the main reservoir of zinc in the retina, zinc may decrease the number of lipofuscin granules that are substrates for autophagy. The triad zinc–autophagy–AMD could explain some controversies associated with population studies on zinc supplementation in AMD as the effect of zinc on AMD may be modulated by genetic background. This aspect was not determined in many studies regarding zinc in AMD. Zinc deficiency induces several events associated with AMD pathogenesis, including increased oxidative stress, lipid peroxidation and the resulting lipofuscinogenesis. The latter requires autophagy, which is impaired. This is a vicious cycle-like reaction that may contribute to AMD progression. Promising results with zinc deficiency and supplementation in AMD patients and animal models, as well as emerging evidence of the importance of autophagy in AMD, are the rationale for future research on the role of autophagy in the role of zinc supplementation in AMD. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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18 pages, 720 KiB  
Review
Experimental Models in Neovascular Age Related Macular Degeneration
by Olivia Rastoin, Gilles Pagès and Maeva Dufies
Int. J. Mol. Sci. 2020, 21(13), 4627; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134627 - 29 Jun 2020
Cited by 27 | Viewed by 12174
Abstract
Neovascular age-related macular degeneration (vAMD), characterized by the neo-vascularization of the retro-foveolar choroid, leads to blindness within few years. This disease depends on angiogenesis mediated by the vascular endothelial growth factor A (VEGF) and to inflammation. The only available treatments consist of monthly [...] Read more.
Neovascular age-related macular degeneration (vAMD), characterized by the neo-vascularization of the retro-foveolar choroid, leads to blindness within few years. This disease depends on angiogenesis mediated by the vascular endothelial growth factor A (VEGF) and to inflammation. The only available treatments consist of monthly intravitreal injections of antibodies directed against VEGF or VEGF/VEGFB/PlGF decoy receptors. Despite their relative efficacy, these drugs only delay progression to blindness and 30% of the patients are insensitive to these treatments. Hence, new therapeutic strategies are urgently needed. Experimental models of vAMD are essential to screen different innovative therapeutics. The currently used in vitro and in vivo models in ophthalmic translational research and their relevance are discussed in this review. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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26 pages, 1723 KiB  
Review
EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration
by Daisy Y. Shu, Erik Butcher and Magali Saint-Geniez
Int. J. Mol. Sci. 2020, 21(12), 4271; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124271 - 16 Jun 2020
Cited by 131 | Viewed by 12379
Abstract
Epithelial–mesenchymal transition (EMT) and endothelial–mesenchymal transition (EndMT) are physiological processes required for normal embryogenesis. However, these processes can be hijacked in pathological conditions to facilitate tissue fibrosis and cancer metastasis. In the eye, EMT and EndMT play key roles in the pathogenesis of [...] Read more.
Epithelial–mesenchymal transition (EMT) and endothelial–mesenchymal transition (EndMT) are physiological processes required for normal embryogenesis. However, these processes can be hijacked in pathological conditions to facilitate tissue fibrosis and cancer metastasis. In the eye, EMT and EndMT play key roles in the pathogenesis of subretinal fibrosis, the end-stage of age-related macular degeneration (AMD) that leads to profound and permanent vision loss. Predominant in subretinal fibrotic lesions are matrix-producing mesenchymal cells believed to originate from the retinal pigment epithelium (RPE) and/or choroidal endothelial cells (CECs) through EMT and EndMT, respectively. Recent evidence suggests that EMT of RPE may also be implicated during the early stages of AMD. Transforming growth factor-beta (TGFβ) is a key cytokine orchestrating both EMT and EndMT. Investigations in the molecular mechanisms underpinning EMT and EndMT in AMD have implicated a myriad of contributing factors including signaling pathways, extracellular matrix remodelling, oxidative stress, inflammation, autophagy, metabolism and mitochondrial dysfunction. Questions arise as to differences in the mesenchymal cells derived from these two processes and their distinct mechanistic contributions to the pathogenesis of AMD. Detailed discussion on the AMD microenvironment highlights the synergistic interactions between RPE and CECs that may augment the EMT and EndMT processes in vivo. Understanding the differential regulatory networks of EMT and EndMT and their contributions to both the dry and wet forms of AMD can aid the development of therapeutic strategies targeting both RPE and CECs to potentially reverse the aberrant cellular transdifferentiation processes, regenerate the retina and thus restore vision. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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19 pages, 2767 KiB  
Review
Circadian Rhythms in Exudative Age-Related Macular Degeneration: The Key Role of the Canonical WNT/β-Catenin Pathway
by Alexandre Vallée, Yves Lecarpentier, Rodolphe Vallée, Rémy Guillevin and Jean-Noël Vallée
Int. J. Mol. Sci. 2020, 21(3), 820; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030820 - 27 Jan 2020
Cited by 14 | Viewed by 4070
Abstract
Age-related macular degeneration (AMD) is considered as the main worldwide cause of blindness in elderly adults. Exudative AMD type represents 10 to 15% of macular degeneration cases, but is the main cause of vision loss and blindness. Circadian rhythm changes are associated with [...] Read more.
Age-related macular degeneration (AMD) is considered as the main worldwide cause of blindness in elderly adults. Exudative AMD type represents 10 to 15% of macular degeneration cases, but is the main cause of vision loss and blindness. Circadian rhythm changes are associated with aging and could further accelerate it. However, the link between circadian rhythms and exudative AMD is not fully understood. Some evidence suggests that dysregulation of circadian functions could be manifestations of diseases or could be risk factors for the development of disease in elderly adults. Biological rhythms are complex systems interacting with the environment and control several physiological pathways. Recent findings have shown that the dysregulation of circadian rhythms is correlated with exudative AMD. One of the main pathways involved in exudative AMD is the canonical WNT/β-catenin pathway. Circadian clocks have a main role in some tissues by driving the circadian expression of genes involved in physiological and metabolic functions. In exudative AMD, the increase of the canonical WNT/β-catenin pathway is enhanced by the dysregulation of circadian rhythms. Exudative AMD progression is associated with major metabolic reprogramming, initiated by aberrant WNT/β-catenin pathway, of aerobic glycolysis. This review focuses on the interest of circadian rhythm dysregulation in exudative AMD through the aberrant upregulation of the canonical WNT/β-catenin pathway. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
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