title: Pharmacological chaperone for α-crystallin partially restores transparency in cataract models.
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 α-crystallins.
authors.affiliation: Departments of Pathology, Biological Chemistry, and Medicinal Chemistry and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Leah N
authors.initials: LN
authors.lastname: Makley
authors.affiliation: Departments of Pathology, Biological Chemistry, and Medicinal Chemistry and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: McMenimen
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: DeVree
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Goldman
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Brittney N
authors.initials: BN
authors.lastname: McGlasson
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA, USA.
authors.forename: Ponni
authors.initials: P
authors.lastname: Rajagopal
authors.affiliation: Departments of Pathology, Biological Chemistry, and Medicinal Chemistry and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Dunyak
authors.affiliation: Center for Chemical Genomics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: McQuade
authors.affiliation: Departments of Pathology, Biological Chemistry, and Medicinal Chemistry and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Thompson
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Sunahara
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA, USA.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Klevit
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA. andley@vision.wustl.edu.
authors.forename: Usha P
authors.initials: UP
authors.lastname: Andley
authors.affiliation: 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.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors / Q000737:chemistry; D000818:Animals; D002152:Calorimetry, Differential Scanning; D002386:Cataract / Q000188:drug therapy* / Q000235:genetics; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D011487:Protein Conformation / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D038202:alpha-Crystallin A Chain / Q000737:chemistry* / Q000235:genetics; D038203:alpha-Crystallin B Chain / Q000737:chemistry* / Q000235:genetics
chemical_list: D000682:Amyloid; C525420:Cryab protein, mouse; D006888:Hydroxycholesterols; D038202:alpha-Crystallin A Chain; D038203:alpha-Crystallin B Chain; C007997:25-hydroxycholesterol