| Literature DB >> 26365380 |
Dorota Skowronska-Krawczyk1, Ling Zhao2, Jie Zhu3, Robert N Weinreb1, Guiqun Cao4, Jing Luo1, Ken Flagg1, Sherrina Patel1, Cindy Wen1, Martin Krupa1, Hongrong Luo1, Hong Ouyang2, Danni Lin1, Wenqiu Wang5, Gen Li4, Yanxin Xu4, Oulan Li6, Christopher Chung1, Emily Yeh1, Maryam Jafari1, Michael Ai1, Zheng Zhong7, William Shi1, Lianghong Zheng8, Michal Krawczyk1, Daniel Chen1, Catherine Shi1, Carolyn Zin1, Jin Zhu1, Pamela L Mellon9, Weiwei Gao10, Ruben Abagyan1, Liangfang Zhang10, Xiaodong Sun11, Sheng Zhong12, Yehong Zhuo7, Michael G Rosenfeld13, Yizhi Liu14, Kang Zhang15.
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.Entities:
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Year: 2015 PMID： 26365380 PMCID： PMC4648709 DOI： 10.1016/j.molcel.2015.07.027
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970