Novel roles for α-crystallins in retinal function and disease

Abstract

α-Crystallins are key members of the superfamily of small heat shock proteins that have been studied in detail in the ocular lens. Recently, novel functions for α-crystallins have been identified in the retina and in the retinal pigmented epithelium (RPE). αB-Crystallin has been localized to multiple compartments and organelles including mitochondria, golgi apparatus, endoplasmic reticulum and nucleus. α-Crystallins are regulated by oxidative and endoplasmic reticulum stress, and inhibit apoptosis-induced cell death. α-Crystallins interact with a large number of proteins that include other crystallins, and apoptotic, cytoskeletal, inflammatory, signaling, angiogenic, and growth factor molecules. Studies with RPE from αB-crystallin deficient mice have shown that αB-crystallin supports retinal and choroidal angiogenesis through its interaction with vascular endothelial growth factor. αB-Crystallin has also been shown to have novel functions in the extracellular space. In RPE, αB-crystallin is released from the apical surface in exosomes where it accumulates in the interphotoreceptor matrix and may function to protect neighboring cells. In other systems administration of exogenous recombinant αB-crystallin has been shown to be anti-inflammatory. Another newly described function of αB-crystallin is its ability to inhibit β-amyloid fibril formation. α-Crystallin mini-chaperone peptides have been identified that elicit anti-apoptotic function in addition to being efficient chaperones. Generation of liposomal particles and other modes of nanoencapsulation of these minipeptides could offer great therapeutic advantage in ocular delivery for a wide variety of retinal degenerative, inflammatory and vascular diseases including age related macular degeneration and diabetic retinopathy.

αB-Crystallin Regulates Subretinal Fibrosis by Modulation of Epithelial-Mesenchymal Transition

“…14 EMT can occur through nuclear translocation of proteins, such as b-catenin, NF-kB, Notch, R-SMADs, and SMAD4, which regulate SNAIL gene expression. 35 We hypothesized that the effect of aB-crystallin modulation on EMT can be mediated by a change in nuclear translocation of these proteins.…”

Antiapoptotic Properties of α-Crystallin–Derived Peptide Chaperones and Characterization of Their Uptake Transporters in Human RPE Cells

“…However, recent studies have identified several novel functions for aA-and aBcrystallins in retina and other tissues in addition to their wellrecognized chaperone function. 2 Both a-crystallins are expressed in RPE cells and in the retina; higher expression of aBcrystallin was found in the RPE while aA-crystallin was found mostly in photoreceptors and astroglial and Müller cells. 3,4 Furthermore, aB-crystallin was shown to be upregulated with several stress stimuli and to translocate to nuclei and mitochondrial compartments of RPE cells.…”

“…3,5 Microarray and proteomic analysis and histological studies have revealed that a-crystallin accumulates in drusen. 2,6,7 Subsequent studies demonstrated the expression of aB-crystallin in RPE cells overlying drusen. 2,8 and aB-crystallin has been suggested to be a biomarker for AMD.…”

“…2,6,7 Subsequent studies demonstrated the expression of aB-crystallin in RPE cells overlying drusen. 2,8 and aB-crystallin has been suggested to be a biomarker for AMD. 8 Since overexpression of full length aB-crystallin reduced susceptibility to oxidative stress-induced apoptosis in RPE cells, 9,10 we suggested that aB-crystallin may have therapeutic potential.…”

“…8 Since overexpression of full length aB-crystallin reduced susceptibility to oxidative stress-induced apoptosis in RPE cells, 9,10 we suggested that aB-crystallin may have therapeutic potential. 5 Since full length aB-crystallin has limited entry into nonstressed cells, 2,5 we considered the possibility that peptides of aB-crystallin may retain antiapoptotic activity while having enhanced cellular uptake.…”