Circadian Rhythms in Exudative Age-Related Macular Degeneration: The Key Role of the Canonical WNT/β-Catenin Pathway

Vallée, Alexandre; Lecarpentier, Yves; Vallée, Rodolphe; Guillevin, Rémy; Vallée, Jean-Noël

doi:10.3390/ijms21030820

Cited by 20 publications

(12 citation statements)

References 169 publications

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“…Dysregulation of the circadian clock also regulates the WNT/β-catenin pathway, malfunction of which is also connected to exudative wet AMD. (83) The gut microbiome regulates circadian rhythm in the brain; (84) but, we provide the first evidence that the gut microbiome can also affect the circadian circuit in the retina.…”

Section: Discussionmentioning

confidence: 95%

High Throughput RNA Sequencing of Germ-Free Mouse Retina Reveals Metabolic Pathways Involved in the Gut-Retina Axis

Nadeem

Xie

Movahedan

et al. 2020

Preprint

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Background and aimsConnections between the gut microbiome and retinal diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), retinopathy of prematurity (ROP), and primary open-angle glaucoma (POAG) are recently being established. Communication between the gut microbiome and retina, referred to as the gut-retina axis, has been proposed; however, the biologic pathways and mediators involved in the interactions have not yet been elucidated. Using high-throughput RNA sequencing (RNA-seq) of whole retinas, we compare the retinal transcriptome from germ-free (GF) and specific pathogen-free (SPF) mice to investigate effects of the gut-microbiome on both retinal gene expression and biologic pathways.MethodsRNA was extracted from whole retinas of GF and SPF mice (four animals per group) and cDNA libraries were created. RNA-seq was performed on NovaSEQ6000 using the paired-end method. After preprocessing the RNA-seq data, gene expression value was calculated by count per million (CPM). The differentially expressed genes (DEGs) were identified with edgeR Bioconductor analysis of expression data. Functional enrichment and protein-protein interaction (PPI) network analyses were created for the differentially expressed genes (DEGs).ResultsRNA-sequencing reveals a cohort of 396 DEGs, of which, 173 are upregulated and 223 are downregulated in GF mouse retina. Enrichment analysis reveals that the DEGs are involved in glucocorticoid effects, transcription factor binding, cytoskeletal stability, lipid metabolism, and mitogen-activated protein kinase (MAPK). Multiple biologic pathways, including obesity/metabolic syndrome, longevity, and 5’ AMP-activated protein kinase (AMPK) signaling pathway are affected in the GF retinas. PPARG1a (PGC1a) gene is involved in 12 of the 16 significantly modulated pathways. Proteins with the most number of interactions in the PPI are E1A binding protein P300(EP300), forkhead box O3(FOXO3) and PGC1a.ConclusionsTo our knowledge, this is the first study demonstrating the involvement of the gut microbiome in driving the retinal transcriptome, providing evidence for the presence of a gut-retina axis. Future studies are needed to define the precise role of the gut-retina axis in the pathogenesis of retinal diseases.

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Section: Discussionmentioning

confidence: 95%

High Throughput RNA Sequencing of Germ-Free Mouse Retina Reveals Metabolic Pathways Involved in the Gut-Retina Axis

Nadeem

Xie

Movahedan

et al. 2020

Preprint

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“…Metabolic dysfunction is strongly correlated with accelerated aging and eye-disease (e.g. diabetic retinopathy) [8, 9]. Declines in the circadian amplitude of clocks within the eye have been reported in wild-type mice with age and in models of diabetic retinopathy, which may further exacerbate disease pathology [10, 11].…”

Section: Supplemental Discussionmentioning

confidence: 99%

Dietary restriction andclockdelay eye aging to extend lifespan inD. melanogaster

Hodge

Meyerhof

Katewa

et al. 2021

Preprint

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Many vital processes in the eye are under circadian regulation, and circadian dysfunction has emerged as a potential driver of eye aging. Dietary restriction is one of the most robust lifespan-extending therapies and amplifies circadian rhythms with age. Herein, we demonstrate that dietary restriction extends lifespan in D. melanogaster by promoting circadian homeostatic processes that protect the visual system from age- and light-associated damage. Disrupting circadian rhythms in the eye by inhibiting the transcription factor, Clock (CLK), or CLK-output genes, accelerated visual senescence, induced a systemic immune response, and shortened lifespan. Flies subjected to dietary restriction were protected from the lifespan-shortening effects of photoreceptor activation. Inversely, photoreceptor inactivation, achieved via mutating rhodopsin or housing flies in constant darkness, primarily extended lifespan in flies reared on a high-nutrient diet. Our findings establish the eye as a diet-sensitive modulator of lifespan and indicate that vision is an antagonistically pleiotropic process that contributes to organismal aging.

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“…Instead, PRKAA2 (known as AMPKα2) expression, another protein known to phosphorylate β-catenin [36], was upregulated (Figure 4B), suggesting a possible crosstalk between AMPK and the Wnt/β-catenin signaling pathway in inflammation-induced RPE. Phosphorylation of β-catenin on Ser-552 and its involvement in activation of aerobic glycolysis for production of angiogenic factors have been previously described in various diseases such as cancer and AMD [37][38][39]. A similar β-catenin phosphorylation response was observed during an oxidative stress-induced detrimental cellular dedifferentiation process in mouse RPE [40].…”

Section: Discussionmentioning

confidence: 56%

A Comprehensive Proteomic and Phosphoproteomic Analysis of Retinal Pigment Epithelium Reveals Multiple Pathway Alterations in Response to the Inflammatory Stimuli

Song

Han

Lee

et al. 2020

IJMS

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Overwhelming and persistent inflammation of retinal pigment epithelium (RPE) induces destructive changes in the retinal environment. However, the precise mechanisms remain unclear. In this study, we aimed to investigate RPE-specific biological and metabolic responses against intense inflammation and identify the molecular characteristics determining pathological progression. We performed quantitative analyses of the proteome and phosphoproteome of the human-derived RPE cell line ARPE-19 after treatment with lipopolysaccharide (LPS) for 45 min or 24 h using the latest isobaric tandem-mass tags (TMTs) labeling approach. This approach led to the identification of 8984 proteins, of which 261 showed a 1.5-fold change in abundance after 24 h of treatment with LPS. A parallel phosphoproteome analysis identified 20,632 unique phosphopeptides from 3207 phosphoproteins with 3103 phosphorylation sites. Integrated proteomic and phosphoproteomic analyses showed significant downregulation of proteins related to mitochondrial respiration and cell cycle checkpoint, while proteins related to lipid metabolism, amino acid metabolism, cell-matrix adhesion, and endoplasmic reticulum (ER) stress were upregulated after LPS stimulation. Further, phosphorylation events in multiple pathways, including MAPKK and Wnt/β-catenin signalings, were identified as involved in LPS-triggered pathobiology. In essence, our findings reveal multiple integrated signals exerted by RPE under inflammation and are expected to give insight into the development of therapeutic interventions for RPE disorders.

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Circadian Rhythms in Exudative Age-Related Macular Degeneration: The Key Role of the Canonical WNT/β-Catenin Pathway

Cited by 20 publications

References 169 publications

High Throughput RNA Sequencing of Germ-Free Mouse Retina Reveals Metabolic Pathways Involved in the Gut-Retina Axis

High Throughput RNA Sequencing of Germ-Free Mouse Retina Reveals Metabolic Pathways Involved in the Gut-Retina Axis

Dietary restriction andclockdelay eye aging to extend lifespan inD. melanogaster

A Comprehensive Proteomic and Phosphoproteomic Analysis of Retinal Pigment Epithelium Reveals Multiple Pathway Alterations in Response to the Inflammatory Stimuli

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