Therapeutic Potential of α-Crystallins in Retinal Neurodegenerative Diseases

Abstract

The chaperone and anti-apoptotic activity of α-crystallins (αA- and αB-) and their derivatives has received increasing attention due to their tremendous potential in preventing cell death. While originally known and described for their role in the lens, the upregulation of these proteins in cells and animal models of neurodegenerative diseases highlighted their involvement in adaptive protective responses to neurodegeneration associated stress. However, several studies also suggest that chronic neurodegenerative conditions are associated with progressive loss of function of these proteins. Thus, while external supplementation of α-crystallin shows promise, their potential as a protein-based therapeutic for the treatment of chronic neurodegenerative diseases remains ambiguous. The current review aims at assessing the current literature supporting the anti-apoptotic potential of αA- and αB-crystallins and its potential involvement in retinal neurodegenerative diseases. The review further extends into potentially modulating the chaperone and the anti-apoptotic function of α-crystallins and the use of such functionally enhanced proteins for promoting neuronal viability in retinal neurodegenerative disease.

Keywords: alpha-crystallin; neurodegeneration; oxidative stress; recombinant proteins.

Figure 1

Mechanistic analyses of α-crystallin mediated cytoprotection. Abbreviation list: cyt c, cytochrome c; Apaf1, apoptotic protease activating factor 1; eIF-2α, eukaryotic translation initiation factor 2α; ATF4, activating transcription factor 4; CHOP, C/EBP homologous protein; XBP1, X-box binding protein; IRE1, Inositol requiring enzyme 1; PERK, Protein kinase R-like ER kinase; ER, endoplasmic reticulum; UPR, unfolded protein response.