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

被引：77

作者：

Skowronska-Krawczyk, Dorota ^{[1
,2
]}

Zhao, Ling ^{[1
,2
,3
]}

Zhu, Jie ^{[1
,2
,4
]}

Weinreb, Robert N. ^{[1
,2
]}

Cao, Guiqun ^{[5
]}

Luo, Jing ^{[1
,2
]}

Flagg, Ken ^{[1
,2
]}

Patel, Sherrina ^{[1
,2
]}

Wen, Cindy ^{[1
,2
]}

Krupa, Martin ^{[1
,2
]}

Luo, Hongrong ^{[1
,2
]}

Ouyang, Hong ^{[1
,2
,3
]}

Lin, Danni ^{[1
,2
]}

Wang, Wenqiu ^{[2
,6
]}

Li, Gen ^{[5
]}

Xu, Yanxin ^{[5
]}

Li, Oulan ^{[5
,7
]}

Chung, Christopher ^{[1
,2
]}

Yeh, Emily ^{[1
,2
]}

Jafari, Maryam ^{[1
,2
]}

Ai, Michael ^{[1
,2
]}

Zhong, Zheng ^{[3
]}

Shi, William ^{[1
,2
]}

Zheng, Lianghong ^{[7
]}

Krawczyk, Michal ^{[1
,2
]}

Chen, Daniel ^{[1
,2
]}

Shi, Catherine ^{[1
,2
]}

Zin, Carolyn ^{[1
,2
]}

Zhu, Jin ^{[1
,2
]}

Mellon, Pamela L. ^{[8
]}

Gao, Weiwei ^{[9
]}

Abagyan, Ruben ^{[1
,2
]}

Zhang, Liangfang ^{[9
]}

Sun, Xiaodong ^{[6
]}

Zhong, Sheng ^{[10
]}

Zhuo, Yehong ^{[3
]}

Rosenfeld, Michael G. ^{[11
]}

Liu, Yizhi ^{[3
]}

Zhang, Kang ^{[1
,2
,3
,5
,10
,12
]}

机构：

[1] Univ Calif San Diego, Dept Ophthalmol, Shiley Eye Inst, La Jolla, CA 92093 USA

[2] Univ Calif San Diego, Inst Engn Med, La Jolla, CA 92093 USA

[3] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China

[4] Fourth Mil Med Univ, Xijing Hosp, Dept Ophthalmol, Xian 710032, Peoples R China

[5] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Mol Med Res Ctr, Chengdu 610041, Sichuan, Peoples R China

[6] Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 1, Dept Ophthalmol, Shanghai 20080, Peoples R China

[7] Guangzhou KangRui Biol Pharmaceut Technol Co Ltd, Guangzhou 510005, Guangdong, Peoples R China

[8] Univ Calif San Diego, Dept Reprod Med, La Jolla, CA 92093 USA

[9] Univ Calif San Diego, Dept Nanoengn, La Jolla, CA 92093 USA

[10] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA

[11] Univ Calif San Diego, Sch Med, Howard Hughes Med Inst, La Jolla, CA 92093 USA

[12] Vet Adm Healthcare Syst, San Diego, CA 92093 USA

来源：

MOLECULAR CELL | 2015年 / 59卷 / 06期

基金：

瑞士国家科学基金会;

关键词：

TRANSCRIPTION FACTORS; MACULAR DEGENERATION; SENESCENT CELLS; HOMEOBOX GENE; MICE LACKING; SUSCEPTIBILITY; ASSOCIATION; EXPRESSION;

D O I：

10.1016/j.molcel.2015.07.027

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：931 / 940

页数：10

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