Modulation of Exosome Release for Functional Restoration in Age-related Retinal Disorders Age-related Macular Degeneration (AMD)

This research project examines how disassembly and release of desmosome and hemidesmosome components via exosomes from retinal pigmented epithelium (RPE) may contribute to early pathogenic events in age-related macular degeneration (AMD). The review synthesizes literature and novel findings showing that the RPE, which forms the outer blood–retinal barrier and provides essential metabolic and nutrient support to photoreceptors, is a principal locus of disease-associated change in AMD. Klingeborn and coauthors highlight that, like other epithelia, RPE cells possess multiple junctional complexes, including desmosomes and hemidesmosomes, which maintain tissue integrity and polarization.

Under chronic oxidative stress conditions relevant to AMD, the authors report that exosomes released from the basolateral side of RPE cells contain desmosome and hemidesmosome proteins, suggesting active shedding of junctional components in response to stress. The review addresses exosomes — nanoscale lipid-bilayer vesicles produced by a dedicated cellular machinery — as carriers of signaling molecules and cellular waste, and emphasizes their polarized release from both apical and basal RPE surfaces. The presence of junctional proteins in basolaterally released exosomes under oxidative challenge raises the possibility that exosome-mediated removal of structural components contributes to junctional dismantling and loss of epithelial phenotype. Klingeborn and colleagues contextualize these observations within pathways of ubiquitination, lysosomal and proteasomal processing, and cellular waste management.

They explore whether targeted disassembly and exosomal export of desmosome and hemidesmosome proteins could be an upstream event that predisposes RPE cells to epithelial–mesenchymal transition (EMT), a process implicated in tissue remodeling and degeneration. Beyond describing composition and mechanisms, the review considers the functional consequences of exosome-mediated junctional shedding for RPE homeostasis and photoreceptor support. The authors discuss how lysosomal and/or proteasomal overload might intersect with exosome pathways to influence the balance between cellular clearance and pathological release of structural proteins. Importantly, they identify multiple molecular nodes — including exosome biogenesis, ubiquitination pathways, and lysosomal/proteasomal function — as potential targets for therapeutic modulation aimed at intervening in pre-symptomatic or early-stage AMD. Klingeborn et al. conclude by summarizing current knowledge about desmosome and hemidesmosome disassembly in the RPE, its intersection with exosome biology, and the potential role of these events in promoting EMT and early AMD pathology.