title: Lanosterol reverses protein aggregation in cataracts.
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.
authors.affiliation: 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.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Xiang-Jun
authors.initials: XJ
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yi-Bo
authors.initials: YB
authors.lastname: Xi
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Li-Dan
authors.initials: LD
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Ouyang
authors.affiliation: Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Sherrina H
authors.initials: SH
authors.lastname: Patel
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Danni
authors.initials: D
authors.lastname: Lin
authors.affiliation: Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Frances
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Flagg
authors.affiliation: 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.
authors.forename: Huimin
authors.initials: H
authors.lastname: Cai
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Gen
authors.initials: G
authors.lastname: Li
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Guiqun
authors.initials: G
authors.lastname: Cao
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Wen
authors.affiliation: Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chung
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Yandong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Austin
authors.initials: A
authors.lastname: Qiu
authors.affiliation: Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Yeh
authors.affiliation: 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.
authors.forename: Wenqiu
authors.initials: W
authors.lastname: Wang
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Seanna
authors.initials: S
authors.lastname: Grob
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Su
authors.affiliation: State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Harry Christianto
authors.initials: HC
authors.lastname: Tjondro
authors.affiliation: State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Xi-Juan
authors.initials: XJ
authors.lastname: Zhao
authors.affiliation: Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Hongrong
authors.initials: H
authors.lastname: Luo
authors.affiliation: Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Hou
authors.forename: J
authors.initials: J
authors.lastname: Jefferson
authors.affiliation: Department of Biochemistry, University of California Riverside, Riverside, California 92521, USA.
authors.forename: P
authors.initials: P
authors.lastname: Perry
authors.affiliation: 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.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Gao
authors.affiliation: King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Igor
authors.initials: I
authors.lastname: Kozak
authors.affiliation: Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: David
authors.initials: D
authors.lastname: Granet
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Yingrui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Sun
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Liangfang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yong-Bin
authors.initials: YB
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D001483:Base Sequence; D002386:Cataract / Q000151:congenital / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002648:Child; D003459:Crystallins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D004285:Dogs; D005260:Female; D006801:Humans; D007810:Lanosterol / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D007908:Lens, Crystalline / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D010375:Pedigree; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000682:Amyloid; D003459:Crystallins; D050505:Mutant Proteins; D066329:Protein Aggregates; D007810:Lanosterol