ArticleMolecular cell2015
P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma.
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Article in Molecular cell, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers, 5 of them syntheses that pooled it.
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60citing papers in PubMed, 5 pooled it
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Who cites it
60 citing papers in PubMed, 5 syntheses or guidelines pooled it, 95 citations in OpenAlex.
- Association of Gene Polymorphisms with Normal Tension Glaucoma: A Systematic Review and Meta-Analysis.Genes · 2024Pooled it
- Novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation.Cell reports. Medicine · 2024Pooled it
- Cellular senescence and chronological age in various human tissues: A systematic review and meta-analysis.Aging cell · 2020Pooled it
- A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci.Nature communications · 2018Pooled it
- New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.Human molecular genetics · 2017Pooled it
- Historical Context for Cellular Senescence, Epigenetic Remodeling, and Lipid Metabolism in Ocular Aging.Investigative ophthalmology & visual science · 2026Article
- The aging eye: navigating molecular mechanisms and innovative interventions.Biogerontology · 2026Review
- Genetic Link Across Species: SIX6, a Major Human Glaucoma Gene, Confers Susceptibility to Glaucoma in Shiba-Inu Dogs.Investigative ophthalmology & visual science · 2026Article
- FOXP2-Dependent Vulnerability of RGCs Under Acute Ocular Hypertension.Molecular neurobiology · 2025Article
- The role of SIX6 gene in juvenile open-angle glaucoma: a subtle contributor to the mutational landscape.Japanese journal of ophthalmology · 2025Article
- PRMT5 Regulates Senescence in Retinal Ganglion Cells by Targeting the Wnt/β-Catenin Signaling Cascade.Investigative ophthalmology & visual science · 2025Article
- Glial-mediated immune modulation in glaucomatous neurodegeneration: mechanisms and therapeutic implications.Frontiers in immunology · 2025Review
- Structural framework to address variant-gene relationship in primary open-angle glaucoma.Vision research · 2025Review
- Review
- Retinal ganglion cell circuits and glial interactions in humans and mice.Trends in neurosciences · 2024Review
- SenMayo transcriptomic senescence panel highlights glial cells in the ageing mouse and human retina.npj aging · 2024Article
- Diabetes Renders Photoreceptors Susceptible to Retinal Ischemia-Reperfusion Injury.Investigative ophthalmology & visual science · 2024Article
- Therapeutic targeting of senescent cells in the CNS.Nature reviews. Drug discovery · 2024Review
- The Impact of Aging on Ocular Diseases: Unveiling Complex Interactions.Aging and disease · 2024Review
- Mendelian randomization implicates causal association between epigenetic age acceleration and age-related eye diseases or glaucoma endophenotypes.Clinical epigenetics · 2024Article
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Authors and funding
39 authors at 5 institutions in 2 countries.
Dorota Skowronska-KrawczykShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Ling ZhaoShiley 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.
Jie ZhuShiley 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.
Robert N WeinrebShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Guiqun CaoMolecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China.
Jing LuoShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Ken FlaggShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Sherrina PatelShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Cindy WenShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Martin KrupaShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Hongrong LuoShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Hong OuyangShiley 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.
Danni LinShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Wenqiu WangShiley 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.
Gen LiMolecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China.
Yanxin XuMolecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China.
Oulan LiMolecular 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.
Christopher ChungShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Emily YehShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Maryam JafariShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Michael AiShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Zheng ZhongState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
William ShiShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Lianghong ZhengGuangzhou KangRui Biological Pharmaceutical Technology Company Ltd., Guangzhou 510005, China.
Michal KrawczykShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Daniel ChenShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Catherine ShiShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Carolyn ZinShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Jin ZhuShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Pamela L MellonDepartment of Reproductive Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Weiwei GaoDepartment of Nanoengineering, University of California, San Diego, La Jolla, CA 92093, USA.
Ruben AbagyanShiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Liangfang ZhangDepartment of Nanoengineering, University of California, San Diego, La Jolla, CA 92093, USA.
Xiaodong SunDepartment of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China.
Sheng ZhongInstitute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Yehong ZhuoState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
Michael G RosenfeldHoward Hughes Medical Institute, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Yizhi LiuState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. Electronic address: yzliu62@yahoo.com.
Kang ZhangShiley 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.
University of California San Diego · USSun Yat-sen University · CNSichuan University · CNShanghai Jiao Tong University · CNHoward Hughes Medical Institute · US
Funding
VIRAL MALIGNANCYP30CA023100 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI DIANE M SIMEONE · 1985 to 2026
$124.9MYeast Genetics and Stress Response Genes-BiomedicalP42ES010337 · NIEHS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI TUKEY, ROBERT H · 2000 to 2022
$69.8MTransgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI PETER J TONTONOZ · 2003 to 2026
$40.4MThe Interaction of Neuroendocrine Repro. Function and Metabolic SignalingU54HD012303 · NICHD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MELLON, PAMELA L · 1999 to 2013
$18.0MVision BiostatisticsP30EY022589 · NEI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Derek Stuart Welsbie · 2012 to 2026
$10.3MTraining Program in Basic Clinical GeneticsT32GM008666 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HAMILTON, BRUCE A · 1998 to 2021
$8.6MThe Role of FSH in Female InfertilityP50HD012303 · NICHD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MELLON, PAMELA L · 1985 to 2020
$7.5MxADAGES III: Contribution of genotype to glaucoma phenotype in African AmericansR01EY023704 · NEI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ROTTER, JEROME I, WEINREB, ROBERT N · 2013 to 2017
$6.3MMacromolecular DockingR01GM071872 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ABAGYAN, RUBEN · 2004 to 2017
$4.2MNEUROSECRETORY GENE EXPRESSION IN THE HYPOTHALAMUSR01DK044838 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MELLON, PAMELA L · 1991 to 2011
$3.8MELOVL4 and Retinal DiseaseR01EY014428 · NEI · UNIVERSITY OF UTAH · PI ZHANG, KANG · 2002 to 2011
$3.4MGENETICS OF MACULAR DEGENERATIONR01EY014448 · NEI · UNIVERSITY OF UTAH · PI ZHANG, KANG · 2003 to 2007
$2.6MBLRD VA I01 BX001898NCI NIH HHS P30 CA023100NEI NIH HHS P30 EY022589NEI NIH HHS P30EY022589NEI NIH HHS R01 EY014428NEI NIH HHS R01 EY014448NEI NIH HHS R01 EY018660NEI NIH HHS R01EY023704NHGRI NIH HHS R01HG008135NICHD NIH HHS P50 HD012303NICHD NIH HHS R01 HD072754NICHD NIH HHS R01 HD082567NICHD NIH HHS U54 HD012303NIDDK NIH HHS P30 DK063491NIDDK NIH HHS R01 DK044838NIEHS NIH HHS P42 ES010337NIGMS NIH HHS R01 GM071872NIGMS NIH HHS T32 GM008666
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.
Indexed as
Amino Acid SequenceAnimalsCase-Control StudiesCell DeathCell LineCyclin-Dependent Kinase Inhibitor p16Glaucoma, Open-AngleHomeodomain ProteinsHumansMice, Inbred C57BLMice, KnockoutMolecular Sequence DataMutation, MissenseRetinal Ganglion CellsTrans-ActivatorsUp-RegulationCyclin-Dependent Kinase Inhibitor p16Homeodomain ProteinsSIX6 protein, humanTrans-Activators
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