Molecular mechanism of retinal ganglion cells degeneration and neuroprotection
Glaucoma is a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age, and genetics. Glaucoma 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. We found that the genetic effect of the SIX6 risk variant is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform INK4a). We further showed that __p16Ink4a elevated expression is linked to retinal ganglion cells (RGCs) aging and death. The p16Ink4a gene is repressed in most normal adult tissues, and becomes activated only at times of tissue damage, cellular stress or aging. In young healthy organisms expression of p16INK4a is low or undetectable, but it increases dramatically in most tissues during natural aging. Consistent with this, the activation of p16INK4a is observed in most senescent cells. Interestingly, markers of cellular senescence dramatically increase in glaucomatous human eye and in mouse models, including elevated secretion of deleterious senescence associated secretory phenotype (SASP) molecules. During our talk we will present the evidence that removal of the senescent cells using transgenic mouse model protects the RGCs from cell death providing preliminary data for future investigations aiming at finding senolytic drugs that can be used to treat glaucoma patients. .