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

被引：190

作者：

Makley, Leah N. ^{[1
,2
,3
,4
]}

McMenimen, Kathryn A. ^{[1
,2
,3
,4
]}

DeVree, Brian T. ^{[6
]}

Goldman, Joshua W. ^{[5
]}

McGlasson, Brittney N. ^{[5
]}

Rajagopal, Ponni ^{[7
]}

Dunyak, Bryan M. ^{[1
,2
,3
,4
]}

McQuade, Thomas J. ^{[8
]}

Thompson, Andrea D. ^{[1
,2
,3
,4
]}

Sunahara, Roger ^{[6
]}

Klevit, Rachel E. ^{[7
]}

Andley, Usha P. ^{[5
]}

Gestwicki, Jason E. ^{[1
,2
,3
,4
,8
]}

机构：

[1] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA

[5] Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA

[6] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA

[7] Univ Washington, Dept Biochem, Seattle, WA 98195 USA

[8] Univ Michigan, Ctr Chem Genom, Ann Arbor, MI 48109 USA

来源：

SCIENCE | 2015年 / 350卷 / 6261期

关键词：

AMYLOID FIBRIL FORMATION; B-CRYSTALLIN; DISEASE; PROTEINS; AGGREGATION; PREVENTION;

D O I：

10.1126/science.aac9145

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：674 / 677

页数：4

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