An Eye on Age-Related Macular Degeneration: The Role of MicroRNAs in Disease Pathology

Abstract

Age-related macular degeneration (AMD) is the primary cause of blindness in developed countries, and is the third leading cause worldwide. Emerging evidence suggests that beside environmental and genetic factors, epigenetic mechanisms, such as microRNA (miRNA) regulation of gene expression, are relevant to AMD providing an exciting new avenue for research and therapy. MiRNAs are short, non-coding RNAs thought to be imperative for coping with cellular stress. Numerous studies have analyzed miRNA dysregulation in AMD patients, although with varying outcomes. Four studies which profiled dysregulated circulating miRNAs in AMD yielded unique sets, and there is only minimal overlap in ocular miRNA profiling of AMD. Mouse models of AMD, including oxygen-induced retinopathy and laser-induced choroidal neovascularization, showed similarities to some extent with miRNA patterns in AMD. For example, miR-146a is an extensively researched miRNA thought to modulate inflammation, and was found to be upregulated in AMD mice and cellular systems, but also in human AMD retinae and vitreous humor. Similarly, mir-17, miR-125b and miR-155 were dysregulated in multiple AMD mouse models as well as in human AMD plasma or retinae. These miRNAs are thought to regulate angiogenesis, apoptosis, phagocytosis, and inflammation. A promising avenue of research is the modulation of such miRNAs, as the phenotype of AMD mice could be ameliorated with antagomirs or miRNA-mimic treatment. However, before meaningful strides can be made to develop miRNAs as a diagnostic or therapeutic tool, reproducible miRNA profiles need to be established for the various clinical outcomes of AMD.

Fig. 1

Word-cloud representation of words found in abstracts related to the search term “miRNAs and AMD”. All words with an occurrence greater than 4 are plotted and their relative abundance is indicated by the size of the respective word. Figure was plotted with Tagxedo (http://www.tagxedo.com/app.html) using words from the abstracts of 21 publications related to miRNAs in AMD [, , , , , –, , , , , , –110]

Fig. 2

Interaction between AMD related miRNAs and genes, pathways and tissues. We selected four miRNAs (plotted in blue) with the most evidence for an involvement in AMD and used Tarbase v7.0 [111] to extract genes (plotted in yellow) with validated interactions with those miRNAs. Genes that are regulated by at least three out of four miRNAs were used to search for significantly enriched pathways using WebGestalt [112]. Pathways containing at least six of these genes and being significantly enriched (Bonferroni corrected p value <0.01) are plotted in purple. The role of the miRNAs in AMD pathology was evaluated in different tissues and/or mouse models (plotted in green)