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Mandy K. Losiewicz, Patrice E. Fort; Diabetes Impairs the Neuroprotective Properties of Retinal Alpha-crystallins. Invest. Ophthalmol. Vis. Sci. 2011;52(9):5034-5042. doi: 10.1167/iovs.10-6931.
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α-Crystallins are small heat shock proteins that regulate cellular damage and cell survival. Expression of the proteins of the crystallin superfamily in the retina and their role in neuronal cell survival were investigated in two animal models of diabetes and retinal neurons in culture.
Crystallin expression was assessed in streptozotocin-induced and Ins2 Akita diabetic mice using iTRAQ methodology and validated using immunoblotting. Protein–protein interactions, solubility properties, and subcellular localization of αA- and αB-crystallins were further analyzed in vivo and in a retinal neuronal cell model using immunoprecipitation and fractionation methods. Survival of retinal neurons to metabolic stress after overexpression and knock-down of α-crystallins was used to measure their neuroprotective properties.
All 10 of the crystallins identified in retinal lysates from both models of type 1 diabetes were strongly upregulated, coinciding with increased retinal cell death and expression of proapoptotic proteins Bax and Bcl-Xs. Diabetes strongly reduces the chaperone function of α-crystallins by reducing their solubility and disrupting the normal interaction of α-crystallins with Bax. The same properties disrupted by diabetes were confirmed to be critical for the neuroprotective effect of the overexpression of α-crystallins in retinal neurons in culture.
Both chemically and genetically induced diabetic models are characterized by upregulation of α-, β-, and γ-crystallins in the retina. Despite being overexpressed, the molecular properties of α-crystallins are disrupted by diabetes and contribute to the loss of neuroprotective function. Identification and prevention of these alterations could lead to the emergence of new therapies for diabetic retinopathy.
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