Lanosterol reverses protein aggregation in cataracts
Lanosterol reverses protein aggregation in cataracts
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DOI：
10.1038/nature14650
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发表时间：
2015-07-30
期刊：
影响因子：
64.8
通讯作者：
Zhang, Kang
中科院分区：
文献类型：
--
作者：
Zhao, Ling;Chen, Xiang-Jun;Zhang, Kang
人类透镜主要由晶状体蛋白组成，该晶状体蛋白组装成高度有序的、相互作用的宏观结构，该宏观结构对于透镜的透明度和折射率至关重要。蛋白质内或蛋白质间相互作用的任何破坏都会改变这种微妙的结构，暴露疏水表面，从而导致蛋白质聚集和白内障形成。白内障是全世界最常见的致盲原因，影响数千万人（1），目前唯一的治疗方法是手术摘除白内障晶状体。透镜蛋白防止聚集和保持透镜透明度的精确机制在很大程度上是未知的。羊毛甾醇是一种富含于透镜中的两亲分子。它是由羊毛甾醇合酶（LSS）在胆固醇合成途径的关键环化反应中合成的。在这里，我们确定了两个不同的纯合LSS错义突变（W581R和G588S）在两个家庭广泛的先天性白内障。这两种突变都影响高度保守的氨基酸残基，并损害LSS的关键催化功能。野生型而非突变型LSS的工程化表达防止各种引起白内障的突变晶体蛋白的细胞内蛋白聚集。处理羊毛甾醇，而不是胆固醇，显着降低了预先形成的蛋白质聚集体在体外和细胞转染实验。我们进一步表明，羊毛甾醇治疗可以降低白内障的严重程度，并增加透明度，在体外解剖兔白内障晶状体和白内障的严重程度，在体内的狗。我们的研究确定羊毛甾醇是预防透镜蛋白聚集的关键分子，并指出了白内障预防和治疗的新策略。
The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra-or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people(1), and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.