Type of the Pape : Review 1 2 Impaired cargo clearance in the Retinal Pigment

Chronic degeneration of the Retinal Pigment Epithelium (RPE) is a precursor to 22 pathological changes in the outer retina. The RPE monolayer, which lies beneath the 23 neuroretina, daily internalises and digests large volumes of spent photoreceptor outer 24 segments. Impaired cargo handling and processing in the endocytic/phagosome and 25 autophagy pathways leads to the accumulation of lipofuscin and N-retinylidene-N26 retinylethanolamine aggregates and chemically-modified compounds such as 27 malondialdehyde and 4-hydroxynonenal within RPE. These contribute to increased 28 proteolytic and oxidative stress, resulting in irreversible damage to post-mitotic RPE cells 29 and development of blinding conditions such as Age-related Macular Degeneration, 30 Stargardt disease and Choroideremia. Here, we review how impaired cargo handling in the 31 RPE results in their dysfunction, discuss new findings from our laboratory and consider how 32 newly discovered roles for lysosomes and the autophagy pathway could provide insights 33 into retinopathies. Studies of these dynamic, molecular events have also been spurred on 34 by recent advances in optics and imaging technology. Mechanisms underpinning lysosomal 35 impairment in other degenerative conditions including storage disorders, α-synuclein 36 pathologies and Alzheimer’s disease are also discussed. Collectively, these findings help 37 transcend conventional understanding of these intracellular compartments as simple waste 38 disposal bags to bring about a paradigm shift in the way lysosomes are perceived. 39