Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration

Abstract

Maintenance of protein homeostasis, also referred to as “Proteostasis”, integrates multiple pathways that regulate protein synthesis, folding, translocation, and degradation. Failure in proteostasis may be one of the underlying mechanisms responsible for the cascade of events leading to age-related macular degeneration (AMD). This review covers the major degradative pathways (ubiquitin-proteasome and lysosomal involvement in phagocytosis and autophagy) in the retinal pigment epithelium (RPE) and summarizes evidence of their involvement in AMD. Degradation of damaged and misfolded proteins via the proteasome occurs in coordination with heat shock proteins. Evidence of increased content of proteasome and heat shock proteins in retinas from human donors with AMD is consistent with increased oxidative stress and extensive protein damage with AMD. Phagocytosis and autophagy share key molecules in phagosome maturation as well as degradation of their cargo following fusion with lysosomes. Phagocytosis and degradation of photoreceptor outer segments ensures functional integrity of the neural retina. Autophagy rids the cell of toxic protein aggregates and defective mitochondria. Evidence suggesting a decline in autophagic flux includes the accumulation of autophagic substrates and damaged mitochondria in RPE from AMD donors. An age-related decrease in lysosomal enzymatic activity inhibits autophagic clearance of outer segments, mitochondria, and protein aggregates, thereby accelerating the accumulation of lipofuscin. This cumulative damage over a person’s lifetime tips the balance in RPE from a state of para-inflammation, which strives to restore cell homeostasis, to the chronic inflammation associated with AMD.

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

“…The accumulation of AGEs and glucose in the retina has been associated with other conditions of hyperglycemia, notably diabetic retinopathy, and some of the phenotypes noted in this work, such as RPE thinning, RPE vacuolation, photoreceptor degeneration, and thinning of the inner retinal layer, were also observed in humans and experimental models of diabetic retinopathy (33,(53)(54)(55)(56)(57)(58)(59). Glycation results in the dysfunction of structural proteins and impaired protein-editing machineries, including autophagy and the ubiquitin proteolytic systems, functions that are required for the degradation of phagosomes and AGEs (11,29,60). Combined, insufficient protein editing leads to the accelerated accumulation of damaged proteins and lipofuscin and to cytotoxicity, all of which we observe in HG mice.…”

“…These features are associated with impaired degradation of phagocytosed photoreceptor outer segments, possibly via autophagy ( Fig. S4B) (29).Together, our data indicate that HG mice show photoreceptor cell damage and RPE abnormalities that highly resemble human dry AMD and retina aging. Most of these AMDf were prevented or reversed by consuming the LG diet or by switching from the HG diet to the LG diet during maturity.…”

Absence of collagen XVIII in mice causes age-related insufficiency in retinal pigment epithelium proteostasis

“…The accumulation of ub-marked proteins is often used as evidence for proteasome inhibition. Lysosomal autophagy is a central clearance system functioning together with the proteasomes (Ferrington et al 2015). The formation of the autophagosome from the phagophore can be divided into four different phases, i.e.…”

“…folding, translocation, and degradation. In addition to increased oxidative stress and the presence of inflammation, a failure in proteostasis may be one of the underlying mechanisms responsible for the cascade of events leading to RPE degeneration and the development of AMD (Ferrington et al 2015;Xu and Ren 2015;Kauppinen et al 2016). RPE cells ingest and degrade the used tips of photoreceptor outer segments and thus clear them from the tissue (Rakoczy et al 1994).…”

Effect of ARMS2 gene polymorphism on intravitreal ranibizumab treatment for neovascular age-related macular degeneration

“…The two main types of AMD are dry type AMD and neovascular type AMD. Neovascular AMD is characterized by the invasion of subretinal pigment epithelium and subretinal spaces by choroidal neovascularization, and geographic atrophy is typified by the degeneration of the choriocapillaris, Bruch's membrane, retinal pigment epithelium, and retina (Danis et al, 2015;Feeny et al, 2015;Schütze et al, 2015;Ferrington et al, 2016).…”