| First Author | Watson GW | Year | 2010 |
| Journal | Biochem Biophys Res Commun | Volume | 401 |
| Issue | 2 | Pages | 192-6 |
| PubMed ID | 20833134 | Mgi Jnum | J:165851 |
| Mgi Id | MGI:4838690 | Doi | 10.1016/j.bbrc.2010.09.023 |
| Citation | Watson GW, et al. (2010) Activation of the unfolded protein response by a cataract-associated alphaA-crystallin mutation. Biochem Biophys Res Commun 401(2):192-6 |
| abstractText | alphaA-crystallin is a lens chaperone that plays an essential role in the transparency and refractive properties of the lens. Mutations in alphaA-crystallin have been associated with the development of hereditary cataracts. The R49C mutation of alphaA-crystallin (alphaA-R49C) was identified in a four-generation Caucasian family with hereditary cataracts. The alphaA-R49C protein forms larger-than-normal oligomers in the lens and has decreased solubility. This aberrant alphaA-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 alphaA-R49C using immunoblot analysis of lens extracts. We found that expression of the endoplasmic reticulum (ER) chaperone, BiP, was 5-fold higher in homozygous alphaA-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 alphaA-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 alphaA-R49C lenses. |
