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Patrice E. Fort, Erich A. Heise, Lauren Marozas; Progressive Impact Of Diabetes On Retinal Neuroprotection By Alpha-crystallins. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5416.
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To better understand how the natural adaptive mechanisms of protection of the retina are impaired by diabetes and more specifically how diabetes modulates the action of alpha-crystallin proteins in retinal cells. Whereas we showed that alpha-crystallins are neuroprotective in retinal neuron in culture and overexpressed in retinal tissues during diabetes, diabetes still increases retinal cell death.
Mice lacking either one, or both, of the alpha-crystallins were used to analyze how alpha-crystallins affect retinal cell survival and retinal function in control conditions and in response to diabetes. Retinal function was analyzed using non-invasive methods such as OCT, pupillometry and ERG measurements whereas specific retinal cell survival was analyzed using cell-death assay and immunohistochemistry. Further analysis of the impact of diabetes and the selective absence of alphaA- or alphaB-crystallins on retinal cells was performed using biochemical methods and proteomic analysis.
We demonstrated that the diabetes-induced crystallin upregulation is not a general stress response leading to the induction of all heat-shock proteins. It is rather an adaptive mechanism that becomes negated through different post-translational modifications. We performed a preliminary characterization of the retina of mice lacking either alphaA- or alphaB-crystallins, and showed that in non-stressed conditions, their retina do not present any anatomical or functional defects. We then demonstrated that the absence of alphaA- and alphaB-crystallin led to a larger increase in retinal cell death during diabetes with different properties. We also showed that alpha-crystallins are targeted for post-translational modifications in the retina during diabetes. Using biochemical and proteomic method, we identified and studied specific alphaA- and alphaB-crystallin phosphorylation sites.
This work clearly demonstrates the primary and direct impact of alpha-crystallins on retinal cell survival in response to diabetes. These results clearly suggest that alphaA- and alphaB-crystallin have a primary neuroprotective function which is progressively impaired during diabetes. This study demonstrates how diabetes can prevent the action of intrinsic protective mechanisms and how understanding such mechanisms is critical in order to prevent loss of vision in patients with diabetes.
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