Journal Article

Pharmacological chaperone for α-crystallin partially restores transparency in cataract models

Gestwicki, Jason E., McGlasson, Brittney N., McMenimen, Kathryn A., Dunyak, Bryan M., Goldman, Joshua W., Thompson, Andrea D., Sunahara, Roger, Klevit, Rachel E., Makley, Leah N., DeVree, Brian T., Rajagopal, Ponni, Andley, Usha P., McQuade, Thomas J.

2015

Overview

Cataracts reduce vision in 50% of individuals over 70 years of age and are a common form of blindness worldwide. Cataracts are caused when damage to the major lens crystallin proteins causes their misfolding and aggregation into insoluble amyloids. Using a thermal stability assay, we identified a class of molecules that bind α-crystallins (cryAA and cryAB) and reversed their aggregation in vitro. The most promising compound improved lens transparency in the R49C cryAA and R120G cryAB mouse models of hereditary cataract. It also partially restored protein solubility in the lenses of aged mice in vivo and in human lenses ex vivo. These findings suggest an approach to treating cataracts by stabilizing α-crystallins.

• Publisher: American Association for the Advancement of Science
• Subject: Agglomeration / alpha-Crystallin A Chain - chemistry / alpha-Crystallin A Chain - genetics / alpha-Crystallin B Chain - chemistry / alpha-Crystallin B Chain - genetics / Amyloid - antagonists & inhibitors / Amyloid - chemistry / Animals / Blindness / Calorimetry, Differential Scanning / Cataract - drug therapy / Cataract - genetics / Cataracts / Crystal structure / Disease Models, Animal / Gene Knock-In Techniques / Humans / Hydroxycholesterols - chemistry / Hydroxycholesterols - pharmacology / Hydroxycholesterols - therapeutic use / Lenses / Mice / Protein Conformation - drug effects / Protein Stability - drug effects / Proteins / Vision