• A Corrigendum to this article was published on 26 August 2015

Abstract

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 people1, 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.

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Acknowledgements

We thank the study participants for their support. We thank G. Hannum, M. Kruppa, J. H. Shin, J. Mei, H. Zheng, F. Xu, J. Zhang, M. Kircher, J. Shendure, S. J. Fliesler, J. Gleeson, X.-T. Zuo, Y. Li and Y. Ding for their helpful advice during the course of the experiments and data analysis. This work is supported in part by grants from 973 Project (2015CB94600, 2012CB917304), 863 Program (2014AA021604), NSFC (31327901), State Key Laboratory of Ophthalmology, and State Key Laboratory of Membrane Biology.

Author information

Author notes

    • Ling Zhao

    Present address: Institute of Molecular Medicine, Peking University, Beijing 100871, China.

    • Ling Zhao
    • , Xiang-Jun Chen
    • , Jie Zhu
    • , Yi-Bo Xi
    • , Xu Yang
    •  & Li-Dan Hu

    These authors contributed equally to this work.

Affiliations

  1. Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China

    • Ling Zhao
    • , Huimin Cai
    • , Gen Li
    • , Guiqun Cao
    • , Xun Hu
    • , Zhiguang Su
    •  & Kang Zhang
  2. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China

    • Ling Zhao
    • , Hong Ouyang
    • , Ying Lin
    • , Yandong Wang
    • , Yizhi Liu
    •  & Kang Zhang
  3. Shiley Eye Institute and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA

    • Ling Zhao
    • , Jie Zhu
    • , Hong Ouyang
    • , Sherrina H. Patel
    • , Danni Lin
    • , Frances Wu
    • , Ken Flagg
    • , Ying Lin
    • , Daniel Chen
    • , Cindy Wen
    • , Christopher Chung
    • , Austin Qiu
    • , Emily Yeh
    • , Wenqiu Wang
    • , Seanna Grob
    • , Hongrong Luo
    • , Weiwei Gao
    • , David Granet
    • , Liangfang Zhang
    •  & Kang Zhang
  4. State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China

    • Xiang-Jun Chen
    • , Yi-Bo Xi
    • , Li-Dan Hu
    • , Harry Christianto Tjondro
    • , Xi-Juan Zhao
    •  & Yong-Bin Yan
  5. Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China

    • Jie Zhu
  6. BGI-Shenzhen, Shenzhen 518083, China

    • Xu Yang
    • , Xin Jin
    • , Yingrui Li
    •  & Jun Wang
  7. Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China

    • Huimin Cai
    •  & Rui Hou
  8. CapitalBio Genomics Co., Ltd., Dongguan 523808, China

    • Austin Qiu
  9. Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China

    • Wenqiu Wang
    •  & Xiaodong Sun
  10. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA

    • Ruben Abagyan
  11. Department of Biochemistry, University of California Riverside, Riverside, California 92521, USA

    • P. Perry
  12. Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA

    • Weiwei Gao
    • , Liangfang Zhang
    •  & Kang Zhang
  13. King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia

    • Igor Kozak
  14. Veterans Administration Healthcare System, San Diego, California 92093, USA

    • Kang Zhang
  15. Institute of Molecular Medicine, Peking University, Beijing 100871, China

    • Kang Zhang

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Contributions

L.Zhao, Y.Liu., Y.-B.Y., L.Zhang and K.Z. designed the study, interpreted data and wrote the manuscript. L.Z., X.-J.C., J.Z., Y.-B.X., X.Y., L.-D.H, H.O., S.H.P., X.J., D.L., F.W., K.F., H.C., G.L., G.C., Y.Li, D.C., C.W., C.C., Y.W., A.Q., E.Y., W.W., X.H., S.G., Z.S., H.C.T., X.-J.Z., H.L., R.H., J.J.P.P., W.G., I.K., D.G., and X.S. performed the experiments; R.A., Y.Li and J.W. contributed to data analysis and interpretation.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Liangfang Zhang or Yizhi Liu or Yong-Bin Yan or Kang Zhang.

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DOI

https://doi.org/10.1038/nature14650

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