Cataracts: role of the unfolded protein response

Many cataracts are caused by unfolded protein aggregates in highly oxidized lenses, but the underlying mechanisms of their formation are poorly understood. A literature search has shown that many cataractogenic stressors are also endoplasmic reticulum (ER) stressors, which induce the unfolded protein response (UPR) in a wide range of cell types. Since the lumen of the ER is highly oxidized, ER stressors might generate unfolded protein aggregates, which activate the UPR leading to the production of reactive oxygen species (ROS) in lens epithelial cells (LECs). ROS decrease the amount of free glutathione from whole lenses and elicit a more oxidized environment, where unfolded protein aggregates are formed and grown to large protein aggregate particles to scatter light. Recently, we have shown that ER stressors, homocysteine, tunicamycin, Ca(2+) ionophore (A23187), and glucose deprivation induce the UPR in LECs. Here we hypothesize the cataractogenic stressors induce ER stress, initiate the UPR and ROS production in LECs with or without apoptosis and eventually resulted in cataracts.