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首页> 外文期刊>Nature >Lanosterol reverses protein aggregation in cataracts
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Lanosterol reverses protein aggregation in cataracts

机译：羊毛甾醇逆转白内障中的蛋白质聚集

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摘要

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.
机译：人类晶状体主要由结晶蛋白组成，这些蛋白组装成高度有序的，相互作用的宏观结构，对于晶状体的透明度和折射率至关重要。蛋白质间或蛋白质间相互作用的任何破坏都将改变这种脆弱的结构，暴露疏水表面，从而导致蛋白质聚集和白内障形成。白内障是全世界失明的最常见原因，影响着数以千万计的人（1），目前唯一的治疗方法是手术摘除白内障晶状体。晶状体蛋白既能防止聚集又能保持晶状体透明性的确切机制在很大程度上尚不清楚。羊毛甾醇是富含晶状体的两亲分子。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，我们在两个先天性广泛性白内障家族中鉴定出两个不同的纯合LSS错义突变（W581R和G588S）。这两个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。 LSS的野生型而非突变型的工程化表达可防止各种引起白内障的突变型结晶蛋白的细胞内蛋白质聚集。在体外和细胞转染实验中，使用羊毛甾醇而不是胆固醇进行处理均显着降低了预先形成的蛋白质聚集体。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，并在体外对切开的兔白内障晶状体增加透明度，并在狗体内提高白内障的严重程度。我们的研究确定了羊毛甾醇是预防晶状体蛋白聚集的关键分子，并指出了一种预防和治疗白内障的新策略。

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  • 来源
    《Nature》 |2015年第7562期|607-611|共5页
  • 作者

    Zhao Ling; Chen Xiang-Jun; Zhu Jie; Xi Yi-Bo; Yang Xu; Hu Li-Dan; Ouyang Hong; Patel Sherrina H.; Jin Xin; Lin Danni; Wu Frances; Flagg Ken; Cai Huimin; Li Gen; Cao Guiqun; Lin Ying; Chen Daniel; Wen Cindy; Chung Christopher; Wang Yandong; Qiu Austin; Yeh Emily; Wang Wenqiu; Hu Xun; Grob Seanna; Abagyan Ruben; Su Zhiguang; Tjondro Harry Christianto; Zhao Xi-Juan; Luo Hongrong; Hou Rui; Perry J. Jefferson P.; Gao Weiwei; Kozak Igor; Granet David; Li Yingrui; Sun Xiaodong; Wang Jun; Zhang Liangfang; Liu Yizhi; Yan Yong-Bin; Zhang Kang;

  • 作者单位

    Sichuan Univ, Mol Med Res Ctr, State Key Lab Biotherapy, West China Hosp, Chengdu 610041, Peoples R China|Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China|Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA;

    Tsinghua Univ, Sch Life Sci, State Key Lab Membrane Biol, Beijing 100084, Peoples R China;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA|Fourth Mil Med Univ, Xijing Hosp, Dept Ophthalmol, Xian 710032, Peoples R China;

    Tsinghua Univ, Sch Life Sci, State Key Lab Membrane Biol, Beijing 100084, Peoples R China;

    BGI Shenzhen, Shenzhen 518083, Peoples R China;

    Tsinghua Univ, Sch Life Sci, State Key Lab Membrane Biol, Beijing 100084, Peoples R China;

    Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China|Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA;

    BGI Shenzhen, Shenzhen 518083, Peoples R China;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA;

    Sichuan Univ, Mol Med Res Ctr, State Key Lab Biotherapy, West China Hosp, Chengdu 610041, Peoples R China|Guangzhou KangRui Biol Pharmaceut Technol Co, Guangzhou 510005, Guangdong, Peoples R China;

    Sichuan Univ, Mol Med Res Ctr, State Key Lab Biotherapy, West China Hosp, Chengdu 610041, Peoples R China;

    Sichuan Univ, Mol Med Res Ctr, State Key Lab Biotherapy, West China Hosp, Chengdu 610041, Peoples R China;

    Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China|Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA;

    Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA|CapitalBio Genom Co Ltd, Dongguan 523808, Peoples R China;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA|Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 1, Dept Ophthalmol, Shanghai 20080, Peoples R China;

    Sichuan Univ, Mol Med Res Ctr, State Key Lab Biotherapy, West China Hosp, Chengdu 610041, Peoples R China;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA;

    Sichuan Univ, Mol Med Res Ctr, State Key Lab Biotherapy, West China Hosp, Chengdu 610041, Peoples R China;

    Tsinghua Univ, Sch Life Sci, State Key Lab Membrane Biol, Beijing 100084, Peoples R China;

    Tsinghua Univ, Sch Life Sci, State Key Lab Membrane Biol, Beijing 100084, Peoples R China;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA;

    Guangzhou KangRui Biol Pharmaceut Technol Co, Guangzhou 510005, Guangdong, Peoples R China;

    Univ Calif Riverside, Dept Biochem, Riverside, CA 92521 USA;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA|Univ Calif San Diego, Dept Nanoengn, La Jolla, CA 92093 USA;

    King Khalid Eye Specialist Hosp, Riyadh, Saudi Arabia;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA;

    BGI Shenzhen, Shenzhen 518083, Peoples R China;

    Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 1, Dept Ophthalmol, Shanghai 20080, Peoples R China;

    BGI Shenzhen, Shenzhen 518083, Peoples R China;

    Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA|Univ Calif San Diego, Dept Nanoengn, La Jolla, CA 92093 USA;

    Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China;

    Fourth Mil Med Univ, Xijing Hosp, Dept Ophthalmol, Xian 710032, Peoples R China;

    Sichuan Univ, Mol Med Res Ctr, State Key Lab Biotherapy, West China Hosp, Chengdu 610041, Peoples R China|Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China|Univ Calif San Diego, Inst Engn Med, Dept Ophthalmol, La Jolla, CA 92093 USA|Univ Calif San Diego, Inst Engn Med, Biomat & Tissue Engn Ctr, La Jolla, CA 92093 USA|Univ Calif San Diego, Dept Nanoengn, La Jolla, CA 92093 USA|Vet Adm Healthcare Syst, San Diego, CA 92093 USA;

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