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

doi:10.1016/j.bbagen.2015.05.016

Biochimica et Biophysica Acta (BBA) - General Subjects

Volume 1860, Issue 1, Part B, January 2016, Pages 258-268

https://doi.org/10.1016/j.bbagen.2015.05.016 Get rights and content

Highlights

•
α-Crystallin is regulated in retinal development and in oxygen-induced retinopathy.
•
α-Crystallins protect RPE cells from oxidative and ER stress, and autophagy.
•
αB Crystallin regulates angiogenesis by modulation of VEGF.
•
αB Crystallin is secreted via exosomes in RPE.
•
αB crystallin peptides may have therapeutic potential in retinal disease.

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. This article is part of a Special Issue entitled Crystallin biochemistry in health and disease.

Section snippets

Localization of α-crystallins

While αA and αB crystallins are considered to be two subunits of one protein, evidence from studies in the developing ocular lens suggests that each of these two proteins exist and function independently of each other [5]. In initial work on the analysis of αA, αB (as well as β and ɣ) crystallins, Xi et al. [6] found that these crystallins were found in the inner and outer nuclear layers of the retina and the RPE. The distribution of αA crystallin and αB crystallin differed; while αB crystallin

Protection from apoptosis by α-crystallins

As is well known, oxidative stress is one of the key causative factors of AMD. There is evidence that oxidative stress induced inflammation initiates AMD [28]. Most of the studies that address the antiapoptotic function and associated signaling mechanisms of α-crystallins use oxidative stress stimuli as a model for such studies. For example, αB crystallin was shown to protect from cell death induced by oxidative stress as well drugs such as staurosporine and doxorubicin [29]. Work from Arrigo's

Role of α-crystallins in autophagy

Autophagy plays a key role in cellular homeostasis. To maintain normal cellular function, autophagy is often upregulated in response to environmental stresses and excessive organelle damage to facilitate aggregated protein removal. Among the three known autophagic mechanisms [34], chaperone-mediated autophagy (CMA) is relevant to our discussion although the autophagic systems are not completely separated from each other. Further, adverse effects of autophagy have been described in a mouse model

Endoplasmic reticulum (ER) stress

ER is known as the cell's protein factory and is involved in the biosynthesis, post-translational modifications, folding and trafficking of proteins. The importance of ER stress and the unfolded protein response (UPR) in retinal degeneration has recently been reviewed [46]. A number of signaling pathways for UPR have been identified among which the major ones are IRE1, PERK and ATF6 pathways. While there is no direct evidence suggesting that ER stress is linked to AMD, the relationship between

Role of αB crystallin in angiogenesis as a VEGF chaperone

An important area of extensive research is the interaction of αB crystallin with a wide variety of other proteins that include apoptosis related, cytoskeletal, signaling, β-amyloid associated proteins as well as several growth factors. These proteins as well as the nature of their interactions with αB crystallin have been summarized [2] and will not be elaborated here. We will focus on the interaction of αB crystallin with VEGF and regulation of angiogenesis. αB Crystallin predicted poor

αB Crystallin is released from cells via exosomes

Most proteins targeted for release from cells are secreted by the canonical pathway, in which they are inserted co-translationally in to the ER, progress through the golgi apparatus and are released extracellularly [59], [60]. However, all secretion pathways do not follow this route and non-conventional pathways via exosomes exist for release of proteins without signal sequences such as α-crystallins. Exosomes, are non-plasma-membrane-derived vesicles (50–100 nm in diameter), initially contained

Extracellular vesicles for drug delivery

One of the major breakthroughs in this field of exosome research came in 2007 with the discovery of the presence of mRNA and microRNA (miRNA) inside exosomes [69]. Exosomes represent a novel reservoir for biomarker discovery because they contain protein, messenger RNA and microRNA that have been demonstrated to change with the disease state [70], [71], [72]. Further, exosomes are important conveyers of information between cells, through the transmission of various proteins, bioactive lipids and

α-Crystallin and its constitutive peptides as therapeutic molecules

Multiple studies have shown that endogenous α-crystallins are upregulated in neurodegenerative disorders, with some studies demonstrating the lack of α-crystallins leads to severe progression of disease, implying a protective role for these molecules. The antiapoptotic and/or anti-inflammatory effects of recombinant human αA or αB crystallin were successfully demonstrated in several animal disease models such as experimental cataracts, experimental autoimmune encephalomyelitis (EAE), stroke,

Future perspectives

Remarkable advances have been made in elucidating the function of α-crystallins in the retina and RPE in the past few years. One important aspect of αB crystallin action that is of significant interest is its possible extracellular function. Our recent discovery that human RPE cells secrete αB crystallin via exosomes is relevant in this regard. Since our studies showed that the secretion was predominantly apical and thus could provide protection of neighboring RPE and photoreceptor cells this

Acknowledgments

We apologize to researchers in the field whose work could not be cited due to space constraints. This work was supported by Grants EY03040 and EY01545 from the National Eye Institute; and funds from Research to Prevent Blindness, and the Arnold and Mabel Beckman Foundation. We are thankful to Dr. Satoru Kase for generating the data used in Fig. 1 and to Ernesto Barron for help with preparation of the figures.

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^☆: This article is part of a Special Issue entitled Crystallin biochemistry in health and disease.

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

Highlights

Abstract

Background

Scope of review

Major conclusions

General significance

Section snippets

Localization of α-crystallins

Protection from apoptosis by α-crystallins

Role of α-crystallins in autophagy

Endoplasmic reticulum (ER) stress

Role of αB crystallin in angiogenesis as a VEGF chaperone

αB Crystallin is released from cells via exosomes

Extracellular vesicles for drug delivery

α-Crystallin and its constitutive peptides as therapeutic molecules

Future perspectives

Acknowledgments

Prog. Retin. Eye Res.

Prog. Retin. Eye Res.

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Exp. Cell Res.

Eur. J. Cell Biol.

Exp. Cell Res.

J. Biol. Chem.

Exp. Eye Res.

Exp. Eye Res.

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Adv. Drug Deliv. Rev.

Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD

Autophagy

Differential expression of alpha A- and alpha B-crystallin during murine ocular development

Invest. Ophthalmol. Vis. Sci.

A comprehensive analysis of the expression of crystallins in mouse retina

Mol. Vis.

alpha-Crystallin distribution in retinal pigment epithelium and effect of gene knockouts on sensitivity to oxidative stress

Mol. Vis.

Elevated retina-specific expression of the small heat shock protein, alphaA-crystallin, is associated with photoreceptor protection in experimental uveitis

Invest. Ophthalmol. Vis. Sci.

Response of small heat shock proteins in diabetic rat retina

Invest. Ophthalmol. Vis. Sci.

Human retinal pigment epithelium cell changes and expression of alphaB-crystallin: a biomarker for retinal pigment epithelium cell change in age-related macular degeneration

Arch. Ophthalmol.

αB crystallin is apically secreted within exosomes by polarized human retinal pigment epithelium and provides neuroprotection to adjacent cells

PLoS One

Cytoplasmic and nuclear anti-apoptotic roles of αB-crystallin in retinal pigment epithelial cells

PLoS One

Localization of phosphorylated alphaB-crystallin to heart mitochondria during ischemia–reperfusion

Am. J. Physiol. Heart Circ. Physiol.

Heat shock pretreatment inhibited the release of Smac/DIABLO from mitochondria and apoptosis induced by hydrogen peroxide in cardiomyocytes and C2C12 myogenic cells

Cell Stress Chaperones

Small heat shock protein alphaB crystallin binds to p53 to sequester its translocation to mitochondria during hydrogen peroxide-induced apoptosis

Biochem. Biophys. Res. Commun.

Calcium-activated RAF/MEK/ERK signaling pathway mediates p53-dependent apoptosis and is abrogated by alpha B-crystallin through inhibition of RAS activation

Mol. Biol. Cell

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