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Mol Cell. 2015 Sep 17;59(6):931-40. doi: 10.1016/j.molcel.2015.07.027. Epub 2015 Sep 10.

P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma.

Author information

1
Shiley Eye Institute, Department of Ophthalmology and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
2
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.
3
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.
4
Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China.
5
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.
6
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.
7
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
8
Guangzhou KangRui Biological Pharmaceutical Technology Company Ltd., Guangzhou 510005, China.
9
Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
10
Department of Nanoengineering, University of California, San Diego, La Jolla, CA 92093, USA.
11
Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China.
12
Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
13
Howard Hughes Medical Institute, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
14
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. Electronic address: yzliu62@yahoo.com.
15
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.

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.

Comment in

PMID:
26365380
PMCID:
PMC4648709
DOI:
10.1016/j.molcel.2015.07.027
[Indexed for MEDLINE]
Free PMC Article

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