alpha A-crystallin is a lens chaperone that plays an essential role in the transparency and refractive properties of the lens. Mutations in alpha A-crystallin have been associated with the development of hereditary cataracts. The R49C mutation of alpha A-crystallin (alpha A-R49C) was identified in a four-generation Caucasian family with hereditary cataracts. The alpha A-R49C protein forms larger-than-normal oligomers in the lens and has decreased solubility. This aberrant alpha A-R49C oligomerization suggests that protein folding is altered. However, whether activation of the unfolded protein response (UPR) occurs during crystallin mutation-induced cataract formation and whether the UPR causes cell death under these conditions is unclear. We investigated UPR activation in an in vivo mouse model of alpha A-R49C using immunoblot analysis of lens extracts. We found that expression of the endoplasmic reticulum (ER) chaperone, BiP, was 5-fold higher in homozygous alpha A-R49C lenses than in wild type lenses. Analysis of proteins typically expressed during the UPR revealed that ATF-4 and CHOP levels were also higher in homozygous lenses than in wild type lenses, while the opposite was true of ATF-6 and XBP-1. Taken together, these findings show that mutation of alpha A-crystallin induces activation of the UPR during cataract formation. They also suggest that the UPR is an important mediator of cell death observed in homozygous alpha A-R49C lenses. (C) 2010 Elsevier Inc. All rights reserved.