Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

Senabouth, Anne; Daniszewski, Maciej; Lidgerwood, Grace E.; Liang, Helena; Hernández, Damián; Mirzaei, Mehdi; Keenan, Stacey N; Zhang, Ran; Han, Xikun; Neavin, Drew; Rooney, Louise; Sanchez, M Isabel G Lopez; Gulluyan, Lerna; Paulo, João A.; Clarke, Linda; Kearns, Lisa S.; Gnanasambandapillai, Vikkitharan; Chan, Chia-Ling; Nguyen, Uyen; Steinmann, Angela; McCloy, Rachael A.; Farbehi, Nona; Gupta, Vivek; Mackey, David A.; Bylsma, Guy; Verma, Nitin; MacGregor, Stuart; Watt, Matthew J.; Guymer, Robyn H.; Powell, Joseph E.; Hewitt, Alex W.; Pébay, Alice

doi:10.1038/s41467-022-31707-4

Cited by 36 publications

(25 citation statements)

References 141 publications

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“…This finding is presumably the first report of such a difference in a CNV model; it suggests that Adcy1 is involved in CNV formation. On the other hand, we reviewed other transcriptomic studies on CNV and AMD and found that the results of our study did not identify the presence of common genes related to neovascular diseases, such as PNPLA2 , MFGE8 , and DDIT4 ( 27 ). This may be because of the restricted sample numbers used in our study.…”

Section: Discussioncontrasting

confidence: 72%

Proteotranscriptomic analyses reveal distinct interferon-beta signaling pathways and therapeutic targets in choroidal neovascularization

Zhuang

et al. 2023

Front. Immunol.

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AimTo investigate the molecular mechanism underlying the onset of choroidal neovascularization (CNV).MethodsIntegrated transcriptomic and proteomic analyses of retinas in mice with laser-induced CNV were performed using RNA sequencing and tandem mass tag. In addition, the laser-treated mice received systemic interferon-β (IFN-β) therapy. Measurements of CNV lesions were acquired by the confocal analysis of stained choroidal flat mounts. The proportions of T helper 17 (Th17) cells were determined by flow cytometric analysis.ResultsA total of differentially expressed 186 genes (120 up-regulated and 66 down-regulated) and 104 proteins (73 up-regulated and 31 down-regulated) were identified. The gene ontology and KEGG pathway analyses indicated that CNV was mainly associated with immune and inflammatory responses, such as cellular response to IFN-β and Th17 cell differentiation. Moreover, the key nodes of the protein–protein interaction network mainly involved up-regulated proteins, including alpha A crystallin and fibroblast growth factor 2, and were verified by Western blotting. To confirm the changes in gene expression, real-time quantitative PCR was performed. Furthermore, levels of IFN-β in both the retina and plasma, as measured by enzyme-linked immunosorbent assay (ELISA), were significantly lower in the CNV group than in the control group. IFN-β treatment significantly reduced CNV lesion size and promoted the proliferation of Th17 cells in laser-treated mice.ConclusionsThis study demonstrates that the occurrence of CNV might be associated with the dysfunction of immune and inflammatory processes and that IFN-β could serve as a potential therapeutic target.

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Section: Discussioncontrasting

confidence: 72%

Proteotranscriptomic analyses reveal distinct interferon-beta signaling pathways and therapeutic targets in choroidal neovascularization

Zhuang

et al. 2023

Front. Immunol.

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“…Recently, another transcriptome and proteome-based study has identified pathways specifically modulated in GA. Induced pluripotent stem cells (iPSCs) were generated from fibroblasts from a cohort of 43 individuals with GA and 36 controls with genotype data [ 57 ]. In this work from Senabouth et al, mitochondrial dysfunction, and specifically, an increase in Complex I linked to a higher oxygen consumption rate, was identified as a central genetic factor associated with GA.…”

Section: Resultsmentioning

confidence: 99%

Recent Advances in Proteomics-Based Approaches to Studying Age-Related Macular Degeneration: A Systematic Review

García-Quintanilla

Rodríguez-Martínez²,

Bandín-Vilar

et al. 2022

IJMS

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Age-related macular degeneration (AMD) is a common ocular disease characterized by degeneration of the central area of the retina in the elderly population. Progression and response to treatment are influenced by genetic and non-genetic factors. Proteomics is a powerful tool to study, at the molecular level, the mechanisms underlying the progression of the disease, to identify new therapeutic targets and to establish biomarkers to monitor progression and treatment effectiveness. In this work, we systematically review the use of proteomics-based approaches for the study of the molecular mechanisms underlying the development of AMD, as well as the progression of the disease and on-treatment patient monitoring. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guidelines were followed. Proteomic approaches have identified key players in the onset of the disease, such as complement components and proteins involved in lipid metabolism and oxidative stress, but also in the progression to advanced stages, including factors related to extracellular matrix integrity and angiogenesis. Although anti-vascular endothelial growth factor (anti-VEGF)-based therapy has been crucial in the treatment of neovascular AMD, it is necessary to deepen our understanding of the underlying disease mechanisms to move forward to next-generation therapies for later-stage forms of this multifactorial disease.

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“…Other data using different experimental approaches also strongly implicate mitochondrial dysfunction as a pathologic feature of AMD. Supportive data from human donor tissue include ultrastructural defects in RPE mitochondria [ 38 ], altered protein content in RPE mitochondria and choroid/Bruch's membrane [ 39 ], increased mtDNA damage in macular RPE from AMD donors [ 9 , 40 ], and decline in mt ETC proteins and function observed in a recent large-scale proteomic study on differentiated RPE cells from AMD patients [ 41 ]. For example, depletion of mtDNA in the RPE cell line, ARPE-19, using ethidium bromide, resulted in induction of genes indicating a switch in metabolism from oxidative phosphorylation to glycolysis and fatty acid metabolism as a mechanism for maintaining energy production [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Dissecting Regulators of Aging and Age-Related Macular Degeneration in the Retinal Pigment Epithelium

Karunadharma

Kapphahn

Stahl

et al. 2022

Oxidative Medicine and Cellular Longevity

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Age-related macular degeneration (AMD), the leading cause of blindness in elderly populations, involves the loss of central vision due to progressive dysfunction of the retinal pigment epithelium (RPE) and subsequent loss of light-sensing photoreceptors. While age is a key risk factor, not every aged individual develops AMD. Thus, the critical question is what specific cellular changes tip the balance from healthy aging to disease. To distinguish between changes associated with aging and AMD, we compared the RPE proteome in human eye bank tissue from nondiseased donors during aging ( n = 50 , 29-91 years) and in donors with AMD ( n = 36 ) compared to age-matched donors without disease ( n = 28 ). Proteins from RPE cells were separated on two-dimensional gels, analyzed for content, and identified using mass spectrometry. A total of 58 proteins displayed significantly altered content with either aging or AMD. Proteins involved in metabolism, protein turnover, stress response, and cell death were altered with both aging and AMD. However, the direction of change was predominantly opposite. With aging, we detected an overall decrease in metabolism and reductions in stress-associated proteins, proteases, and chaperones. With AMD, we observed upregulation of metabolic proteins involved in glycolysis, TCA, and fatty acid metabolism, with a concurrent decline in oxidative phosphorylation, suggesting a reprogramming of energy utilization. Additionally, we detected upregulation of proteins involved in the stress response and protein turnover. Predicted upstream regulators also showed divergent results, with inhibition of inflammation and immune response with aging and activation of these processes with AMD. Our results support the idea that AMD is not simply advanced aging but rather the culmination of perturbed protein homeostasis, defective bioenergetics, and increased oxidative stress within the aging RPE, exacerbated by environmental factors and the genetic background of an individual.

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Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

Cited by 36 publications

References 141 publications

Proteotranscriptomic analyses reveal distinct interferon-beta signaling pathways and therapeutic targets in choroidal neovascularization

Proteotranscriptomic analyses reveal distinct interferon-beta signaling pathways and therapeutic targets in choroidal neovascularization

Recent Advances in Proteomics-Based Approaches to Studying Age-Related Macular Degeneration: A Systematic Review

Dissecting Regulators of Aging and Age-Related Macular Degeneration in the Retinal Pigment Epithelium

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