Desmosome and Hemidesmosome Release via Exosomes from Retinal Pigmented Epithelium - A Precursor to Epithelial-Mesenchymal Transition in Early AMD?

Purpose: This minireview discusses desmosome and hemidesmosome disassembly and/or internalization and subsequent release via exosomes in retinal pigmented epithelium (RPE) under oxidative stress conditions, and whether it may be a precursor to epithelial-mesenchymal transition in early Age-related Macular Degeneration (AMD).

Methods: Literature review and discussion of novel findings relevant to the focus of the review.

Results: The RPE forms the outer blood-retinal barrier, and like other epithelia it has several different types of cell-cell junctions, such as desmosomes. The RPE provides key metabolic and nutrient support to photoreceptors and the function of normal vision. The RPE is a principal location of disease-associated changes in AMD, due to its essential role in visual homeostasis. Exosomes are lipid bilayer membrane vesicles of nanometer sizes that are released via a dedicated machinery by all cells and carry out a multitude of functions related to cellular signaling and waste management. In the RPE they are released from both the apical and basal sides, and the cargo composition reflects this polarization. We have recently showed that exosomes released from the basolateral side of RPE cells under chronic oxidative stress conditions, contain desmosome and hemidesmosome proteins. Here we discuss the composition of desmosomes and hemidesmosomes in the RPE, the role of exosomes and ubiquitination pathways in their disassembly, and whether this dismantling is a precursor to epithelial-mesenchymal transition. Further considerations include how the exosome-mediated shedding of desmosome and hemidesmosome components is related to lysosomal and/or proteasomal overload, and how these pathways can be modulated to intervene in early stages of AMD.

Conclusions: This review provides an overview of the current knowledge about desmosome and hemidesmosome disassembly in RPE, its intersection with the exosome pathway, and potential role in epithelial-mesenchymal transition. We discuss several potential targets for therapeutic intervention in pre-symptomatic or early-stage AMD in these pathways.