title: P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma.
abstract: Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age, and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the SIX6 risk variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform INK4a). We further show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in p16INK4a expression, with subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing p16INK4a expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis.
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Dorota
authors.initials: D
authors.lastname: Skowronska-Krawczyk
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Weinreb
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China.
authors.forename: Guiqun
authors.initials: G
authors.lastname: Cao
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Luo
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Flagg
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Sherrina
authors.initials: S
authors.lastname: Patel
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Wen
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Krupa
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Hongrong
authors.initials: H
authors.lastname: Luo
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ouyang
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Danni
authors.initials: D
authors.lastname: Lin
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA; 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, Sichuan 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, Sichuan 610041, China.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China; Guangzhou KangRui Biological Pharmaceutical Technology Company Ltd., Guangzhou 510005, China.
authors.forename: Oulan
authors.initials: O
authors.lastname: Li
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chung
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Yeh
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Jafari
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ai
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: William
authors.initials: W
authors.lastname: Shi
authors.affiliation: Guangzhou KangRui Biological Pharmaceutical Technology Company Ltd., Guangzhou 510005, China.
authors.forename: Lianghong
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Krawczyk
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chen
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Shi
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Zin
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Mellon
authors.affiliation: Department of Nanoengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Gao
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.affiliation: Department of Nanoengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Liangfang
authors.initials: L
authors.lastname: Zhang
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: Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Yehong
authors.initials: Y
authors.lastname: Zhuo
authors.affiliation: Howard Hughes Medical Institute, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. Electronic address: yzliu62@yahoo.com.
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Veterans Administration Healthcare System, San Diego, CA 92093, USA. Electronic address: kang.zhang@gmail.com.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016022:Case-Control Studies; D016923:Cell Death; D002460:Cell Line; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D005902:Glaucoma, Open-Angle / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D012165:Retinal Ganglion Cells / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; C491945:SIX6 protein, human; D015534:Trans-Activators