2. Academic Validation
  3. Lanosterol reverses protein aggregation in cataracts

Lanosterol reverses protein aggregation in cataracts

  • Nature. 2015 Jul 30;523(7562):607-11. doi: 10.1038/nature14650.
Ling Zhao 1,  Xiang-Jun Chen 2,  Jie Zhu 3,  Yi-Bo Xi 2,  Xu Yang 4,  Li-Dan Hu 2,  Hong Ouyang 5,  Sherrina H Patel 6,  Xin Jin 4,  Danni Lin 6,  Frances Wu 6,  Ken Flagg 6,  Huimin Cai 7,  Gen Li 8,  Guiqun Cao 8,  Ying Lin 5,  Daniel Chen 6,  Cindy Wen 6,  Christopher Chung 6,  Yandong Wang 9,  Austin Qiu 10,  Emily Yeh 6,  Wenqiu Wang 11,  Xun Hu 8,  Seanna Grob 6,  Ruben Abagyan 12,  Zhiguang Su 8,  Harry Christianto Tjondro 2,  Xi-Juan Zhao 2,  Hongrong Luo 6,  Rui Hou 13,  J Jefferson,  P Perry 14,  Weiwei Gao 15,  Igor Kozak 16,  David Granet 6,  Yingrui Li 4,  Xiaodong Sun 17,  Jun Wang 4,  Liangfang Zhang 15,  Yizhi Liu 9,  Yong-Bin Yan 18,  Kang Zhang 19
Affiliations

Affiliations

  • 1 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [3] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA.
  • 2 State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 3 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
  • 4 BGI-Shenzhen, Shenzhen 518083, China.
  • 5 1] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [2] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA.
  • 6 Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA.
  • 7 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China.
  • 8 Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 9 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
  • 10 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] CapitalBio Genomics Co., Ltd., Dongguan 523808, China.
  • 11 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China.
  • 12 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA.
  • 13 Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China.
  • 14 Department of Biochemistry, University of California Riverside, Riverside, California 92521, USA.
  • 15 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA.
  • 16 King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia.
  • 17 Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China.
  • 18 Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
  • 19 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [3] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [4] Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA [5] Veterans Administration Healthcare System, San Diego, California 92093, USA.
PMID: 26200341 DOI: 10.1038/nature14650
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 people, 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.

Figures