scholarly journals The ocular tissue-specificity of differentially expressed age-related macular degeneration associated genes

2021 ◽  
Author(s):  
Dylan Duchen ◽  
Terri Beaty
Keyword(s):  
Macular Degeneration ◽  
Mrna Expression ◽  
Tissue Specificity ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Differentially Expressed ◽  
Ocular Tissue ◽  
Genome Wide Association Studies ◽  
Ocular Tissues ◽  
Age Related

PurposeAge-related macular degeneration (AMD) is a leading cause of blindness in the developed world. One of the most genetically well-characterized degenerative diseases, genome-wide association studies (GWAS) have identified 52 independent common or rare AMD risk associated variants. While transcriptome-wide association analyses (TWAS) and expression quantitative trait loci (eQTL) efforts have characterized the effects of these AMD-associated genes on mRNA expression in retinal tissue, we aimed to characterize the AMD-associated transcriptional profiles of functionally distinct ocular tissues including the macular and extramacular regions of the retina and the retinal-pigment epithelium (RPE)/choroid.MethodsUsing publicly available microarray data (NCBI GEO accession: GSE29801) comprised of retinal and RPE/choroidal tissue samples from 142 AMD patients and 151 healthy individuals (118 retina and 175 RPE/Choroid samples), tissue-specific differential gene expression analyses were conducted. Transcriptome analyses were focused on 878 genes surrounding known AMD-associated loci.ResultsMany genes which contain clinically significant or causal variants identified via GWAS or TWAS/eQTL studies were significantly differentially expressed and display transcriptional heterogeneity across different subtypes of ocular tissue and retinal geography in AMD-associated tissues.ConclusionThese findings demonstrate the importance of spatial heterogeneity and tissue specificity in the mRNA expression of known AMD-associated genes. Genes known to harbor rare or causal AMD- associated variants are differentially expressed in functionally distinct ocular tissues of AMD patients, suggesting they might contribute to disease regardless of mutation status.

scholarly journals Towards the identification of causal genes for age-related macular degeneration

2019 ◽  
Author(s):  
Fei-Fei Cheng ◽  
You-Yuan Zhuang ◽  
Xin-Ran Wen ◽  
Angli Xue ◽  
Jian Yang ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Association Studies ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association Studies ◽  
Age Related ◽  
Causal Genes ◽  
Trait Locus ◽  
Eqtl Data

AbstractAge-related macular degeneration (AMD) is a leading cause of visual impairment in ageing populations and has no radical treatment or prevention. Although genome-wide association studies (GWAS) have identified many susceptibility loci for AMD, the underlying causal genes remain elusive. Here, we prioritized nine putative causal genes by integrating expression quantitative trait locus (eQTL) data from blood (n = 2,765) with AMD GWAS data (16,144 cases vs. 17,832 controls) and replicated six of them using retina eQTL data (n = 523). Of the six genes, altering expression of cnn2, sarm1 and bloc1s1 led to ocular phenotype, impaired vision and retinal pigment epithelium (RPE) loss in zebrafish. Essential photoreceptor and RPE genes were downregulated in cnn2- and sarm1-knockdown zebrafishes. Through integration of GWAS and eQTL data followed by functional validation, our study reveals potential roles of CNN2, SARM1 and BLOC1S1 in AMD pathogenesis and demonstrates an efficient platform to prioritise causal genes for human complex diseases.

Chemistry, Distribution, and Metabolism of Tomato Carotenoids and Their Impact on Human Health

2002 ◽  
Vol 227 (10) ◽  
pp. 845-851 ◽  
Author(s):  
Frederick Khachik ◽  
Lorena Carvalho ◽  
Paul S. Bernstein ◽  
Garth J. Muir ◽  
Da-You Zhao ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Human Serum ◽  
Macular Degeneration ◽  
Ciliary Body ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Food Products ◽  
Age Related Macular Degeneration ◽  
Ocular Tissues ◽  
Age Related

Recent epidemiological studies have suggested that the consumption of tomatoes and tomato-based food products reduce the risk of prostate cancer in humans. This protective effect has been attributed to carotenoids, which are one of the major classes of phytochemicals in this fruit. The most abundant carotenoid in tomato is lycopene, followed by phytoene, phytofluene, ζ-carotene, -γ-carotene, ß-carotene, neurosporene, and lutein. The distribution of lycopene and related carotenoids in tomatoes and tomato-based food products has been determined by extraction and high-performance liquid chromatography-UV/Visible photodiode array detection. Detailed qualitative and quantitative analysis of human serum, milk, and organs, particularly prostate, have revealed the presence of all the aforementioned carotenoids in biologically significant concentrations. Two oxidative metabolites of lycopene, 2, 6-cyclolycopene-1, 5-diols A and B, which are only present in tomatoes in extremely low concentrations, have been isolated and identified in human serum, milk, organs (liver, lung, breast, liver, prostate, colon) and skin. Carotenoids may also play an important role in the prevention of age-related macular degeneration, cataracts, and other blinding disorders. Among 25 dietary carotenoids and nine metabolites routinely found in human serum, mainly (3R, 3'R, 6'R)-lutein, (3R, 3'R)-zeaxanthin, lycopene, and their metabolites were detected in ocular tissues. In this review we identified and quantified the complete spectrum of carotenoids from pooled human retinal pigment epithelium, ciliary body, iris, lens, and in the uveal tract and in other tissues of the human eye to gain a better insight into the metabolic pathways of ocular carotenoids. Although (3R, 3'R, 6'R)-lutein, (3R, 3'R)-zeaxanthin, and their metabolites constitute the major carotenoids in human ocular tissues, lycopene and a wide range of dietary carotenoids have been detected in high concentrations in ciliary body and retinal pigment epithelium. The possible role of lycopene and other dietary carotenoids in the prevention of age-related macular degeneration and other eye diseases Is discussed.

scholarly journals Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium

2021 ◽  
Vol 118 (30) ◽  
pp. e2103617118
Author(s):  
Brandi L. Williams ◽  
Nathan A. Seager ◽  
Jamie D. Gardiner ◽  
Chris M. Pappas ◽  
Monica C. Cronin ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Macular Degeneration ◽  
Association Studies ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association Studies ◽  
Protective Function ◽  
Age Related ◽  
Increased Risk

Genome-wide association studies have identified the chromosome 10q26 (Chr10) locus, which contains the age-related maculopathy susceptibility 2 (ARMS2) and high temperature requirement A serine peptidase 1 (HTRA1) genes, as the strongest genetic risk factor for age-related macular degeneration (AMD) [L.G. Fritsche et al., Annu. Rev. Genomics Hum. Genet. 15, 151–171, (2014)]. To date, it has been difficult to assign causality to any specific single nucleotide polymorphism (SNP), haplotype, or gene within this region because of high linkage disequilibrium among the disease-associated variants [J. Jakobsdottir et al. Am. J. Hum. Genet. 77, 389–407 (2005); A. Rivera et al. Hum. Mol. Genet. 14, 3227–3236 (2005)]. Here, we show that HTRA1 messenger RNA (mRNA) is reduced in retinal pigment epithelium (RPE) but not in neural retina or choroid tissues derived from human donors with homozygous risk at the 10q26 locus. This tissue-specific decrease is mediated by the presence of a noncoding, cis-regulatory element overlapping the ARMS2 intron, which contains a potential Lhx2 transcription factor binding site that is disrupted by risk variant rs36212733. HtrA1 protein increases with age in the RPE–Bruch’s membrane (BM) interface in Chr10 nonrisk donors but fails to increase in donors with homozygous risk at the 10q26 locus. We propose that HtrA1, an extracellular chaperone and serine protease, functions to maintain the optimal integrity of the RPE–BM interface during the aging process and that reduced expression of HTRA1 mRNA and protein in Chr10 risk donors impairs this protective function, leading to increased risk of AMD pathogenesis. HtrA1 augmentation, not inhibition, in high-risk patients should be considered as a potential therapy for AMD.

scholarly journals Role of amyloid β-peptide in the pathogenesis of age-related macular degeneration

2021 ◽  
Vol 6 (1) ◽  
pp. e000774
Author(s):  
Minwei Wang ◽  
Shiqi Su ◽  
Shaoyun Jiang ◽  
Xinghuai Sun ◽  
Jiantao Wang
Keyword(s):  
Mitochondrial Dysfunction ◽  
Macular Degeneration ◽  
Vision Loss ◽  
Cell Structure ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Amyloid Β ◽  
Age Related Macular Degeneration ◽  
Amyloid Β Peptide ◽  
Age Related

Age-related macular degeneration (AMD) is the most common eye disease in elderly patients, which could lead to irreversible vision loss and blindness. Increasing evidence indicates that amyloid β-peptide (Aβ) might be associated with the pathogenesis of AMD. In this review, we would like to summarise the current findings in this field. The literature search was done from 1995 to Feb, 2021 with following keywords, ‘Amyloid β-peptide and age-related macular degeneration’, ‘Inflammation and age-related macular degeneration’, ‘Angiogenesis and age-related macular degeneration’, ‘Actin cytoskeleton and amyloid β-peptide’, ‘Mitochondrial dysfunction and amyloid β-peptide’, ‘Ribosomal dysregulation and amyloid β-peptide’ using search engines Pubmed, Google Scholar and Web of Science. Aβ congregates in subretinal drusen of patients with AMD and participates in the pathogenesis of AMD through enhancing inflammatory activity, inducing mitochondrial dysfunction, altering ribosomal function, regulating the lysosomal pathway, affecting RNA splicing, modulating angiogenesis and modifying cell structure in AMD. The methods targeting Aβ are shown to inhibit inflammatory signalling pathway and restore the function of retinal pigment epithelium cells and photoreceptor cells in the subretinal region. Targeting Aβ may provide a novel therapeutic strategy for AMD.

scholarly journals Differential Expression of Inflammasome-Related Genes in Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells with or without History of Age-Related Macular Degeneration

2021 ◽  
Vol 22 (13) ◽  
pp. 6800
Author(s):  
Maria Hytti ◽  
Eveliina Korhonen ◽  
Heidi Hongisto ◽  
Kai Kaarniranta ◽  
Heli Skottman ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Retinal Pigment ◽  
Induced Pluripotent Stem Cell ◽  
Retinal Pigment Epithelial Cells ◽  
Age Related Macular Degeneration ◽  
Inflammasome Activation ◽  
Protein Clearance ◽  
Age Related ◽  
Induced Pluripotent ◽  
Pigment Epithelial Cells

Inflammation is a key underlying factor of age-related macular degeneration (AMD) and inflammasome activation has been linked to disease development. Induced pluripotent stem-cell-derived retinal pigment epithelial cells (iPSC-RPE) are an attractive novel model system that can help to further elucidate disease pathways of this complex disease. Here, we analyzed the effect of dysfunctional protein clearance on inflammation and inflammasome activation in iPSC-RPE cells generated from a patient suffering from age-related macular degeneration (AMD) and an age-matched control. We primed iPSC-RPE cells with IL-1α and then inhibited both proteasomal degradation and autophagic clearance using MG-132 and bafilomycin A1, respectively, causing inflammasome activation. Subsequently, we determined cell viability, analyzed the expression levels of inflammasome-related genes using a PCR array, and measured the levels of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and MCP-1 secreted into the medium. Cell treatments modified the expression of 48 inflammasome-related genes and increased the secretion of mature IL-1β, while reducing the levels of IL-6 and MCP-1. Interestingly, iPSC-RPE from an AMD donor secreted more IL-1β and expressed more Hsp90 prior to the inhibition of protein clearance, while MCP-1 and IL-6 were reduced at both protein and mRNA levels. Overall, our results suggest that cellular clearance mechanisms might already be dysfunctional, and the inflammasome activated, in cells with a disease origin.

scholarly journals Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Donita L. Garland ◽  
Eric A. Pierce ◽  
Rosario Fernandez-Godino
Keyword(s):  
Macular Degeneration ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Deposit Formation ◽  
Genetic Ablation ◽  
Age Related ◽  
Complement Dysregulation

AbstractThe complement system plays a role in the formation of sub-retinal pigment epithelial (RPE) deposits in early stages of age-related macular degeneration (AMD). But the specific mechanisms that connect complement activation and deposit formation in AMD patients are unknown, which limits the development of efficient therapies to reduce or stop disease progression. We have previously demonstrated that C3 blockage prevents the formation of sub-RPE deposits in a mouse model of EFEMP1-associated macular degeneration. In this study, we have used double mutant Efemp1R345W/R345W:C5-/- mice to investigate the role of C5 in the formation of sub-RPE deposits in vivo and in vitro. The data revealed that the genetic ablation of C5 does not eliminate the formation of sub-RPE deposits. Contrarily, the absence of C5 in RPE cultures promotes complement dysregulation that results in increased activation of C3, which likely contributes to deposit formation even in the absence of EFEMP1-R345W mutant protein. The results also suggest that genetic ablation of C5 alters the extracellular matrix turnover through an effect on matrix metalloproteinases in RPE cell cultures. These results confirm that C3 rather than C5 could be an effective therapeutic target to treat early AMD.

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