Public Release: 

Compound 'dissolves' protein clumps that cause cataracts

American Association for the Advancement of Science

Identification of a compound that reduces the "cloudiness" associated with cataracts could lead to a new therapeutic for this common, age-related eye disorder. Cataracts are the most frequent cause of blindness in the world and therapy is currently limited to surgery, which is not always available in developing countries. Cataracts occur when crystallin proteins within the lens become damaged, causing them to misfold and aggregate into insoluble clumps. Two abundant lens proteins that play an important role in dissolving other proteins and are also known to contribute to age-related cataracts are αA-crystallin (cryAA) and αB-crystallin (cryAB). Leah Makley et al. therefore sought to identify molecules that would bind and stabilize these crystallins. They noted a distinct difference between the melting point of normal cryAB proteins and a hereditary mutant form (R120G cryAB) that results in misfolding. The team screened 2,450 compounds for a candidate that would normalize the melting transition point of these mutant proteins. They identified compound 29, which "fit" nicely between two subunits of the cryAB protein, effectively stabilizing it. In a test tube, compound 29 was able to prevent the aggregation of R120G cryAB, as well as partially reverse aggregation that had already occurred. Importantly, this molecule partially restored the transparency of cataracts in mice, as well as in samples of human lenses studied ex vivo. A Perspective by Roy Quinlan discusses these findings in more detail.

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Article #20: "Pharmacological chaperone for ?-crystallin partially restores transparency in cataract models," by L.N. Makley; K.A. McMenimen; B.T. DeVree; B.M. Dunyak; T.J. McQuade; A.D. Thompson; R. Sunahara; J.E. Gestwicki at University of Michigan in Ann Arbor, MI; J.W. Goldman; B.N. McGlasson; U.P. Andley at Washington University School of Medicine in St. Louis, MO; P. Rajagopal; R.E. Klevit at University of Washington in Seattle, WA.

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