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

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

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

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 a-crystallins.

Original languageEnglish
Pages (from-to)674-677
Number of pages4
JournalScience
Volume350
Issue number6261
DOIs
StatePublished - Nov 6 2015

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    Makley, L. N., McMenimen, K. A., DeVree, B. T., Goldman, J. W., McGlasson, B. N., Rajagopal, P., Dunyak, B. M., McQuade, T. J., Thompson, A. D., Sunahara, R., Klevit, R. E., Andley, U. P., & Gestwicki, J. E. (2015). Pharmacological chaperone for α-crystallin partially restores transparency in cataract models. Science, 350(6261), 674-677. https://doi.org/10.1126/science.aac9145