Therapeutic Potential of α-Crystallins in Retinal Neurodegenerative Diseases.

Zachary B Sluzala,Ashutosh S Phadte,Patrice E Fort

doi:10.3390/antiox10071001

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.

Highlights

Our observations strongly suggest that an increase in the expression of α-crystallins in diabetes reflects their neuroprotective potential in preventing retinal cell death, disease progression is associated with an alteration of their inherent neuroprotective efficacy, eventually compromising protein function under chronic disease conditions
Media obtained from glial cells expressing the T148 phosphomimetic T148D was shown to have a greater effect in promoting cell survival in comparison to the wild-type protein and the non-phosphorylatable control, T148A
Biochemical analyses of a mutant of αA-crystallin, αA-R21Q, associated with congenital cataract revealed that this gain of function mutation enhanced the survival of ARPE-19 cells under oxidative stress [93]

Summary

The Chaperone and Cytoprotective Function of α-Crystallins

Lens crystallins were first described by Mörner in the later years of the 19th century as constituent proteins that make up the crystalline lens. The α-crystallins, comprise of αA and αB subunits, are encoded by genes CRYAA (αA- on chromosome 21) and CRYAB (αB- on chromosome 11) Both isoforms share about fifty seven percent identity in their protein sequences [15,16]. CRYAB has been classified as a class I HspB gene due to its ubiquitous pattern of expression in a wide range of tissues such as the retina, heart, kidney, skeletal muscles, brain, and skin, with an observed increase in protein expression in response to stress [18,19,20]. Expression of α-crystallins in cells was shown to positively influence their viability under stress, suggesting that the observed chaperone activity of the proteins in vitro translated into their cytoprotective ability under stress [30,31,32,33]. Expression of α-crystallins in cells was shown to positively influence their viability under stress, suggesting that the observed chaperone activity of the proteins in vitro translated into their cytoprotective ability under stress [30,31,32,33]. αA- and αB-crystallin expression has since been shown to correlate with increased cellular survival in the presence of external stressors such as UVA/UVB [34], staurosporine [35], etoposide [35,36], hydrogen peroxide [33,37,38], TNFα [37,38,39,40], and serum starvation/nutrient deprivation [22]

Mechanistic Analyses of the Anti-Apoptotic Function of α-Crystallin

Development of Peptide Mini-Chaperone Derivatives of α-Crystallin

Functional Repertoire of αA- and αB-Crystallins in Ocular Health and Disease

Systemic versus Local Administration of α-Crystallin

Conclusions