A specific phosphorylation regulates the protective role of αA-crystallin in diabetes
Anne Ruebsam, Jennifer E. Dulle, Angela M. Myers, Dhananjay Sakrikar, Katelyn M. Green, Naheed W. Khan, Kevin Schey, Patrice E. Fort
Anne Ruebsam, Jennifer E. Dulle, Angela M. Myers, Dhananjay Sakrikar, Katelyn M. Green, Naheed W. Khan, Kevin Schey, Patrice E. Fort
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Research Article Ophthalmology

A specific phosphorylation regulates the protective role of αA-crystallin in diabetes

Abstract

Neurodegeneration is a central aspect of the early stages of diabetic retinopathy, the primary ocular complication associated with diabetes. While progress has been made to improve the vascular perturbations associated with diabetic retinopathy, there are still no treatment options to counteract the neuroretinal degeneration associated with diabetes. Our previous work suggested that the molecular chaperones α-crystallins could be involved in the pathophysiology of diabetic retinopathy; however, the role and regulation of α-crystallins remained unknown. In the present study, we demonstrated the neuroprotective role of αA-crystallin during diabetes and its regulation by its phosphorylation on residue 148. We further characterized the dual role of αA-crystallin in neurons and glia, its essential role for neuronal survival, and its direct dependence on phosphorylation on this residue. These findings support further evaluation of αA-crystallin as a treatment option to promote neuron survival in diabetic retinopathy and neurodegenerative diseases in general.

Authors

Anne Ruebsam, Jennifer E. Dulle, Angela M. Myers, Dhananjay Sakrikar, Katelyn M. Green, Naheed W. Khan, Kevin Schey, Patrice E. Fort

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Figure 1

Retinal morphology and function of α-crystallin–KO mice.

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Retinal morphology and function of α-crystallin–KO mice. Graphic represe...
Graphic representation of retinal cell death, measured by DNA fragmentation ELISA in whole retinas from WT, αA-crystallin–KO (Ko-CryAA), αB-crystallin–KO (Ko-CryAB), and double-KO (Ko-CryAA/AB) mice at 4, 8, and 12 weeks of diabetes (A). Retinal thickness was measured by optical coherence tomography (OCT) after 2 weeks (B) and by microscopy using histological sections after 4 weeks (C) of diabetes in the same experimental groups. Graphic representation of retinal function, assessed by electroretinogram (ERG) in the same animals, depicting the scotopic b-wave (D) and photopic b-wave amplitude (E) in diabetic WT (gray squares), αA-crystallin–KO (gray diamonds), and αB-crystallin–KO (gray circles) mice compared with nondiabetic controls (black labels) 2, 4, 6, and 8 weeks after diabetes induction. The combined rod-cone responses recorded at +1.09 log cd × s/m2 are reported. Early cataract formation precludes the use of OCT and ERG in double-KO mice. *P ≤ 0.05, **P ≤ 0.01, significantly different from nondiabetic WT mice. #P ≤ 0.05, significantly different from WT diabetic mice. For each time point, a minimum of 8 mice was used for each group reported. Statistical analysis was performed by 1-way ANOVA followed by Student-Newman-Keuls test. D, diabetic.