Pharmacological chaperone for α-crystallin partially restores transparency in cataract models.
Pharmacological chaperone for α-crystallin partially restores transparency in cataract models.
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DOI：
10.1126/science.aac9145
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发表时间：
2015-11-06
期刊：
影响因子：
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通讯作者：
Gestwicki JE
中科院分区：
文献类型：
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作者：
Makley LN;McMenimen KA;DeVree BT;Goldman JW;McGlasson BN;Rajagopal P;Dunyak BM;McQuade TJ;Thompson AD;Sunahara R;Klevit RE;Andley UP;Gestwicki JE
白内障会降低50%的70岁以上人群的视力，是全球常见的失明形式。当对主要透镜晶状体蛋白的损伤导致其错误折叠和聚集成不溶性淀粉样蛋白时，引起白内障。使用热稳定性测定，我们鉴定了一类结合α-晶体蛋白（cryAA和cryAB）并在体外逆转其聚集的分子。最有前途的化合物改善了R49 C cryAA和R120 G cryAB遗传性白内障小鼠模型的透镜透明度。它还部分恢复了老年小鼠和人类晶状体的溶解度。这些发现提示了通过稳定α-晶体蛋白来治疗白内障的方法。
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 solubility in aged mouse and human lenses. These findings suggest an approach to treating cataracts by stabilizing α-crystallins.