Lanosterol reverses protein aggregation in cataracts

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 and Zhang, Kang (2015) Lanosterol reverses protein aggregation in cataracts. Nature, 523 7562: 607-611. doi:10.1038/nature14650

Author 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
Title Lanosterol reverses protein aggregation in cataracts
Journal name Nature   Check publisher's open access policy
ISSN 1476-4687
Publication date 2015-07-30
Year available 2015
Sub-type Article (original research)
DOI 10.1038/nature14650
Open Access Status Not Open Access
Volume 523
Issue 7562
Start page 607
End page 611
Total pages 5
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
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