Publication Date:
2015-11-07
Description:
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 alpha-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 alpha-crystallins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725592/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725592/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Makley, Leah N -- McMenimen, Kathryn A -- DeVree, Brian T -- Goldman, Joshua W -- McGlasson, Brittney N -- Rajagopal, Ponni -- Dunyak, Bryan M -- McQuade, Thomas J -- Thompson, Andrea D -- Sunahara, Roger -- Klevit, Rachel E -- Andley, Usha P -- Gestwicki, Jason E -- EY017370/EY/NEI NIH HHS/ -- EY02687/EY/NEI NIH HHS/ -- EY05681/EY/NEI NIH HHS/ -- GM007767/GM/NIGMS NIH HHS/ -- R01 EY005681/EY/NEI NIH HHS/ -- UL1 TR000433/TR/NCATS NIH HHS/ -- UL1RR024986/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2015 Nov 6;350(6261):674-7. doi: 10.1126/science.aac9145.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Pathology, Biological Chemistry, and Medicinal Chemistry and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA. ; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA. ; Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA. ; Department of Biochemistry, University of Washington, Seattle, WA, USA. ; Center for Chemical Genomics, University of Michigan, Ann Arbor, MI, USA. ; Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA. andley@vision.wustl.edu. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26542570" target="_blank"〉PubMed〈/a〉
Keywords:
Amyloid/antagonists & inhibitors/chemistry
;
Animals
;
Calorimetry, Differential Scanning
;
Cataract/*drug therapy/genetics
;
Disease Models, Animal
;
Gene Knock-In Techniques
;
Humans
;
Hydroxycholesterols/chemistry/*pharmacology/therapeutic use
;
Mice
;
Protein Conformation/drug effects
;
Protein Stability/drug effects
;
alpha-Crystallin A Chain/*chemistry/genetics
;
alpha-Crystallin B Chain/*chemistry/genetics
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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