Alpha crystallins in the retinal pigment epithelium and implications for the pathogenesis and treatment of age-related macular degeneration

Abstract

Background αA- and αB crystallins are principal members of the small heat shock protein family and elicit both a cell protective function and a chaperone function. α-Crystallins have been found to be prominent proteins in normal and pathological retina emphasizing the importance for in-depth understanding of their function and significance. Scope of Review Retinal pigment epithelial cells (RPE) play a vital role in the pathogenesis of age-related macular degeneration (AMD). This review addresses a number of cellular functions mediated by α-crystallins in the retina. Prominent expression of αB crystallin in mitochondria may serve to protect cells from oxidative injury. αB crystallin as secretory protein via exosomes can offer neuroprotection to adjacent RPE cells and photoreceptors. The availability of chaperone-containing minipeptides of αB crystallin could prove to be a valuable new tool for therapeutic treatment of retinal disorders. Major Conclusions α-Crystallins are expressed in cytosol and mitochondria of RPE cells and are regulated during oxygen-induced retinopathy and during development. α-Crystallins protect RPE from oxidative-and ER stress-induced injury and autophagy. αB-Crystallin is a modulator of angiogenesis and vascular endothelial growth factor. αB Crystallin is secreted via exosomal pathway. Minichaperone peptides derived from αB Crystallin prevent oxidant induced cell death and have therapeutic potential. General Significance Overall, this review summarizes several novel properties of α-crystallins and their relevance to maintaining normal retinal function. In particular, the use of α-crystallin derived peptides is a promising therapeutic strategy to combat retinal diseases such as AMD.

Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions

“…Despite differences in experimental approach, all three studies found that patient-derived RPE overexpressed mRNAs and proteins neovascularization. [52][53][54] Under basal conditions, our study demonstrated an increase in annexin A2 mRNA and a decrease in ICAM-1.…”

“…αA and αB crystallins belong to a family of heat shock proteins that have been detected in the RPE‐Bruch's membrane‐choroid complex of AMD patients. These proteins may serve to protect RPE cells from oxidative injury but may also play a role in the progression of angiogenesis in choroidal neovascularization . Under basal conditions, our study demonstrated an increase in annexin A2 mRNA and a decrease in ICAM‐1.…”

SWATH-MS Proteomic Analysis of Oxygen-Induced Retinopathy Reveals Novel Potential Therapeutic Targets

“…26,27 They protect cells from hypoxia and maintain mitochondrial integrity. 26,28 In addition to their neuroprotective role, crystallins also have other roles in vascular biology. 29,30 aB-crystallin functions as a chaperone for VEGFA and is crucial for its proper secretion, which in turn, is crucial for endothelial cell survival in hypoxia.…”

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

“…One explanation for this decreased autophagy might be the accumulation of lipofuscin, a hallmark of aging; this protein is known to suppress lysosomal function and autophagic clearance in RPE cells (Ryhänen et al 2009;Krohne et al 2010;Viiri et al 2013;Mitter et al 2014;Valapala et al 2014;Zhang et al 2015). Autophagy may regulate the traffic of intracellular proteins in exosomes into the extracellular space, which probably contributes to drusen formation (Wang et al 2009;Kannan et al 2016). The cytoplasms of RPE cells showed sporadic to moderate staining in specimens from the wild type mice whereas the corresponding knock-outs showed only sporadic staining in the groups 10-13 months and younger but almost extensive staining in 18 months old mice.…”