Collaborative research between research groups in the US and China has indicated a mechanistic link between high-risk genetic alleles found to be associated with primary open angle glaucoma (POAG) and the death of retinal ganglion cells (RGCs). The results of the new research suggest the genetic effect of a particular variant of the SIX6 gene is enhanced by a separate POAG risk gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform INK4a). The up-regulation of homozygous alleles (CC) of the SIX6 gene appears to increase p16INK4a expression leading to cellular senescence in both animals and humans with elevated IOP. The research, conducted jointly between the University of California’s, Department of Ophthalmology and Institute of Engineering in Medicine in San Diego and the State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China was published in Molecular Cell (http://dx.doi.org/10.1016/j.molcel.2015.07.027)
Glaucoma is estimated to effect almost 60 million people globally and is the most common cause of irreversible blindness in the world. It is more accurately referred to as a group of neuropathies, up to 60 different types, with characteristic loss of optic nerve fibres and subsequent loss of visual field. Primary open angle glaucoma is one of the most frequent types of glaucoma in the Western world with a particularly high risk for families of Afro Caribbean descent. Most POAG patients can be treated medically, either with once-daily prostaglandin analogues or once-daily combination drops of prostaglandin analogues and beta-blockers however, RGC death can progress to partial or complete blindness and the exact disease aetiology that connects glaucoma, elevated IOP and RGC death is not fully understood.
The present US-Chinese research looked at genetic association studies to uncover genetic variants that segregated with the disease. Engineering these variants into cell culture models in the lab allowed researchers to probe the molecular biology revealing how His141 mutations in the SIX6 gene increases the effectiveness with which the transcript activates p16INK4a, ultimately triggering senescence pathways in RGCs. The results of the study appeared to indicate that increased p16INK4a expression is a significant factor in causing cellular-senescence pathways that then lead into RGC degeneration and death. Interfering with these pathways may therefore present new therapeutic opportunities for the development of novel drug approaches to treating the disorder. The authors of the study conclude their report stating that, “[T]aken together, our study shows that SIX6 His variant increases p16INK4a expression upon increased IOP, which in turn causes RGCs to enter into a senescent state and which may lead to increased RGC death in glaucoma. Our study provides important insights into the pathogenesis of glaucoma and suggests future therapeutic strategies based on targeted inhibition of p16INK4a induced cell senescence to prevent and treat glaucoma.”