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

Autor: Makley LN; Departments of Pathology, Biological Chemistry, and Medicinal Chemistry and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA., McMenimen KA; Departments of Pathology, Biological Chemistry, and Medicinal Chemistry and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA., DeVree BT; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA., Goldman JW; Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA., McGlasson BN; Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA., Rajagopal P; Department of Biochemistry, University of Washington, Seattle, WA, USA., Dunyak BM; Departments of Pathology, Biological Chemistry, and Medicinal Chemistry and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA., McQuade TJ; Center for Chemical Genomics, University of Michigan, Ann Arbor, MI, USA., Thompson AD; Departments of Pathology, Biological Chemistry, and Medicinal Chemistry and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA., Sunahara R; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA., Klevit RE; Department of Biochemistry, University of Washington, Seattle, WA, USA., Andley UP; Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA. andley@vision.wustl.edu., Gestwicki JE; Departments of Pathology, Biological Chemistry, and Medicinal Chemistry and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA. Center for Chemical Genomics, University of Michigan, Ann Arbor, MI, USA. andley@vision.wustl.edu.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2015 Nov 06; Vol. 350 (6261), pp. 674-7.
DOI: 10.1126/science.aac9145
Abstrakt: 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.
(Copyright © 2015, American Association for the Advancement of Science.)
Databáze: MEDLINE
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