Experimental analyses of R12C mutant αA-crystallin aggregation and chaperone activity in the presence of calcium: The mechanistic interpretation of diabetes-induced hypercalcemia and cataractogenesis

Calcium level increases significantly in the eye lenses of diabetic patients. This is due to the impairment in the proper membrane influx/efflux of calcium ions occurring as a result of oxidative environment produced by chronic hyperglycemia in diabetes. Therefore, a large amount of calcium ion will accumulate in the intra cellular of the lenticular tissues, inducing different pathogenic reactions in eye lenses which ultimately result in development of cataract diseases. In our study, we evaluated the impact of calcium ion on structure, aggregation propensity and chaperon-like activity of R12C mutant αA-crystallins, using different spectroscopic assessments and SDS-PAGE analysis. A significant reduction in chaperone activity of the mutant αA-crystallin was observed in the presence of calcium ion. Moreover, R12C mutant αA-crystallin demonstrated significant propensity for disulfide-mediated dimerization and aggregation in the presence of calcium, particularly at the elevated temperature. The elevation of calcium levels may also result in activation of calpain which subsequently induced partial hydrolysis of lens crystallins, resulting in protein kinase C inhibition and subsequent increment of the reactive oxygen species level in the lenticular tissues. All these pathological events may contribute in development of lens opacity and cataract diseases in diabetic patients. Moreover, the raise of calcium level in eye lenses is an additional contributory factor accelerating the development of cataract diseases in patients with R12C mutation.

Keywords:

Calcium , αA-crystallin , Aggregation , Chaperone activity , Diabetic cataract