Secretory proteostasis of the retinal pigmented epithelium: Impairment links to age-related macular degeneration

Secretory proteostasis integrates protein synthesis, processing, folding and trafficking pathways that are essential for efficient cellular secretion. For the retinal pigment epithelium (RPE), secretory proteostasis is of vital importance for the maintenance of the structural and functional integrity of apical (photoreceptors) and basal (Bruch's membrane/choroidal blood supply) sides of the environment it resides in. This integrity is achieved through functions governed by RPE secreted proteins, which include extracellular matrix modelling/remodelling, angiogenesis and immune response modulation. Impaired RPE secretory proteostasis affects not only the extracellular environment, but leads to intracellular protein aggregation and ER-stress with subsequent cell death. Ample recent evidence implicates dysregulated proteostasis as a key factor in the development of age-related macular degeneration (AMD), the leading cause of blindness in the developed world, and research aiming to characterise the roles of various proteins implicated in AMD-associated dysregulated proteostasis unveiled unexpected facets of the mechanisms involved in degenerative pathogenesis. This review analyses cellular processes unveiled by the study of the top 200 transcripts most abundantly expressed by the RPE/choroid in the light of the specialised secretory nature of the RPE. Functional roles of these proteins and the mechanisms of their impaired secretion, due to age and genetic-related causes, are analysed in relation to AMD development. Understanding the importance of RPE secretory proteostasis in relation to maintaining retinal health and how it becomes impaired in disease is of paramount importance for the development and assessment of future therapeutic advancements involving gene and cell therapies. •· The retinal pigment epithelium (RPE) spends a huge amount of cellular energy for producing its secretome.•Multiple pathways are employed to allow protein release from RPE cells.•RPE secretory proteins govern multiple processes (apical/basolateral ECM (re)modelling, angiogenesis, immune response).•Altered RPE secretory proteostasis contributes to age- and disease-associated loss of retinal integrity.•Mutated secreted proteins cause intracellular proteotoxicity and ER stress, alongside extracellular proteolytic imbalance.