Repository of proposed pathways and protein–protein interaction networks in age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is one of the commonest causes of sight loss in the elderly population and to date there is no intervention that slows or prevents early AMD disease progressing to blinding neovascularization or geographic atrophy. AMD is a complex disease and factors proposed to contribute to the development and progression of disease include aging, genetics, epigenetics, oxidative stress, pro-inflammatory state, and life-style factors such as smoking, alcohol, and high fat diet. Here, we generate a knowledge repository of pathways and protein-protein interaction (PPI) networks likely to be implicated in AMD pathogenesis, such as complement activation, lipid trafficking and metabolism, vitamin A cycle, oxidative stress, proteostasis, bioenergetics, autophagy/mitophagy, extracellular matrix (ECM) turnover, and choroidal vascular dropout. Two disctinct clusters ermerged from the networks for parainflamation and ECM homeostasis, which may represent two different disease modules underlying AMD pathology. Our analyses also suggest that the disease manifests primarily in RPE/choroid and less in neural retina. The use of standardized syntax when generating maps of these biological processes (SBGN standard) and networks (PSI standard) enables visualization of complex information in graphical programs such as CellDesigner and Cytoscape and enhances reusability and extension of data. The ability to focus onto subnetworks, multiple visualizations and simulation options will enable the AMD research community to computationally model subnetworks or to test experimentally new hypotheses arising from connectivities in the AMD pathway map.npj Aging and Mechanisms of Disease (2020) 6:2 ; https://doi.

Combining Gene–Disease Associations with Single-Cell Gene Expression Data Provides Anatomy-Specific Subnetworks in Age-Related Macular Degeneration

“…An overlap of AMD risk genes with genes associated with other age-related disorders, such as coronary heart disease, diabetes, and Alzheimer's disease, has been noted previously. 5 Corroborating this, we find a high overlap (70%) of the 307 AMD risk genes with genes of other age-related diseases ( Fig. 1D and Supplementary Fig.…”

“…1B), as noticed earlier. 5,15 Indeed, gene expression analyses of composite choroid/RPE and NR tissues obtained from human donor eyes 6 showed that AMD genes rarely belonged to ''expression group A'' (the top 1% of genes with highest transcript abundance), but were more often included in the upper 25% (''group B''), the middle 50% (''group C''), or the lower 25% (''group D'') expression classes ( Supplementary Fig. S3).…”

“…One of the challenges in finding treatments for AMD is that-despite substantial advances in genetics and knowledge about the vast number of pathways and protein-protein interaction (PPI) networks proposed to be involved in the pathogenesis 5 -it is unclear which proteins/pathways and which cells are the optimal drug target(s). Indeed, gene expression data analyses of choroid/RPE and neural retina (NR) tissues obtained from human donor eyes 6 suggested that most of the genes are not expressed tissue specifically and are indeed expressed in most of the nonretinal body tissues.…”

“…Indeed, gene expression data analyses of choroid/RPE and neural retina (NR) tissues obtained from human donor eyes 6 suggested that most of the genes are not expressed tissue specifically and are indeed expressed in most of the nonretinal body tissues. 5 In line with this finding, many of the AMD risk gene products (proteins) have proposed roles in generic cell and tissue homeostasis pathways, such as proteostasis, energy homeostasis, mitophagy, autophagy, and choroidal vascular homeostasis, 5 and are not specifically related to core vision processes (e.g., phototransduction).…”

“…Indeed, gene expression data analyses of choroid/RPE and neural retina (NR) tissues obtained from human donor eyes 6 suggested that most of the genes are not expressed tissue specifically and are indeed expressed in most of the nonretinal body tissues. 5 …”