Genetic Interaction May Be Key to Development and Progression of Glaucoma

Scientists at the University of California, San Diego School of Medicine have elucidated a genetic interaction that may prove key to the development and progression of glaucoma, a blinding neurodegenerative disease that affects tens of millions of people worldwide and is a leading cause of irreversible blindness.

The findings, published in the September 10 online issue of Molecular Cell, suggest a new therapeutic target for treating the eye disease.

Primary open-angle glaucoma (POAG) is the most common form of glaucoma, affecting more than 3 million Americans, primarily after the age of 50. Pressure inside the eye (known as intraocular pressure) and age are the leading risk factors for POAG, resulting in progressive degeneration of retinal ganglion cells, optic nerve damage and eventual vision loss.

Genetics also plays a role. Recent genome-wide association studies have identified two genes – SIX1-SIX6 and p16INK4a – as strongly associated with POAG. SIX6 is required for proper eye development. P16INK4a irreversibly arrests cell growth, a phenomenon called senescence.

In their new paper, principal investigator Kang Zhang, MD, PhD, professor of ophthalmology and chief of Ophthalmic Genetics at Shiley Eye Institute at UC San Diego Health, and colleagues report that some variants of SIX6 boost expression of p16INK4a, which in turn accelerates senescence and death of retinal ganglion cells.

“We also show that high intraocular pressure in glaucoma increases expression of p16INK4a, making it a key integrator of inherent genetic and environmental risk factors that can result in glaucoma,” said Zhang.

The findings suggest that inhibiting p16INK4a could offer a new therapeutic approach for glaucoma, which is currently treated by drugs that lower intraocular pressure. “Although lowering intraocular pressure can slow worsening of the disease, it does not stop it and prevent further cell death or possible blindness,” said co-author Robert N. Weinreb, MD, Distinguished Professor of Ophthalmology and director of the Shiley Eye Institute.

Image of optic nerve in a patient with glaucoma.

This is the optic nerve head of a patient with glaucoma. Credit: UCSD Health.

The authors note that earlier studies in mouse models have shown that selective elimination of p16INK4a-positive senescent cells can prevent or delay age-related tissue deterioration.

According to the UC San Diego team, the next step is to conduct preclinical studies to assess the efficacy and safety of antisense oligonucleotides – strands of synthesized DNA or RNA that can prevent transfer of genetic information – which might inhibit p16INK4a expression and prevent worsening of glaucoma. “If they are effective, we may contemplate a human clinical trial in the future,” Zhang said.

About this genetics research

Co-authors include Dorota Skowronska-Krawczyk, Robert N. Weinreb, Jing Luo, Ken Flagg, Sherrina Patel, Cindy Wen, Martin Krupa, Hongrong Luo, Danni Lin, Wengqiu Wang, Christopher Chung, Emily Yeh, Maryam Jafari, Michael Ai, William Shi, Michael Krawczyk, Daniel Chen, Catherine Shi, Carolyn Zin, and Jin Zhu, Shiley Eye Institute and Institute of Engineering in Medicine, both at UC San Diego; Ling Zhao and Hong Quyang, UC San Diego and Sun Yat-sen University, China; Jie Zhu, UC San Diego and Fourth Military Medical University, China; Guiqun Cao, Gen Li, and Yanxin Xu, Sichuan University, China; Oulan Li, Sichuan University and Shanghai Jiao Tong University, China; Lianghong Zheng, Guangzhou KangRui Biological Pharmaceutical Technology Co., China; Pamela Mellon, Weiwei Gao, Liangfang Zhang, Sheng Zhong, UC San Diego; Zheng Zhong, Yehong Zhuo, and Yizhi Liu, Sun Yat-sen University, China; Xiaodong Sun, Shanghai Jiao Tong University, China; and Michael G. Rosenfeld, Howard Hughes Medical Institute, UC San Diego.

Funding: The research was supported by 973 Program, State Key Laboratory of Ophthalmology, National Institutes of Health, and Research to Prevent Blindness.

Source: Scott LaFee – UCSD
Image Source: The image is credited to UCSD Health.
Original Research: Abstract for “P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma” by Dorota Skowronska-Krawczyk, Ling Zhao, Jie Zhu, Robert N. Weinreb, Guiqun Cao, Jing Luo, Ken Flagg, Sherrina Patel, Cindy Wen, Martin Krupa, Hongrong Luo, Hong Ouyang, Danni Lin, Wenqiu Wang, Gen Li, Yanxin Xu, Oulan Li, Christopher Chung, Emily Yeh, Maryam Jafari, Michael Ai, Zheng Zhong, William Shi, Lianghong Zheng, Michal Krawczyk, Daniel Chen, Catherine Shi, Carolyn Zin, Jin Zhu, Pamela L. Mellon, Weiwei Gao, Ruben Abagyan, Liangfang Zhang, Xiaodong Sun, Sheng Zhong, Yehong Zhuo, Michael G. Rosenfeld, Yizhi Liu, and Kang Zhang in Molecular Cell. Published online September 10 2015 doi:10.1016/j.molcel.2015.07.027


Abstract

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

Highlights
•SIX6 and p16INK4a contribute to POAG genetic risk synergistically
•SIX6 directly regulates p16INK4a expression
•SIX6 and p16INK4a promote retinal ganglion cell senescence and death

Summary
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.

“P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma” by Dorota Skowronska-Krawczyk, Ling Zhao, Jie Zhu, Robert N. Weinreb, Guiqun Cao, Jing Luo, Ken Flagg, Sherrina Patel, Cindy Wen, Martin Krupa, Hongrong Luo, Hong Ouyang, Danni Lin, Wenqiu Wang, Gen Li, Yanxin Xu, Oulan Li, Christopher Chung, Emily Yeh, Maryam Jafari, Michael Ai, Zheng Zhong, William Shi, Lianghong Zheng, Michal Krawczyk, Daniel Chen, Catherine Shi, Carolyn Zin, Jin Zhu, Pamela L. Mellon, Weiwei Gao, Ruben Abagyan, Liangfang Zhang, Xiaodong Sun, Sheng Zhong, Yehong Zhuo, Michael G. Rosenfeld, Yizhi Liu, and Kang Zhang in Molecular Cell. Published online September 10 2015 doi:10.1016/j.molcel.2015.07.027

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