biostudies-literature00580Skowronska-Krawczyk DBLRD VANEI NIH HHSNICHD NIH HHSNIDDK NIH HHSNIEHS NIH HHSNHGRI NIH HHSNCI NIH HHSNIGMS NIH HHS931-40https://www.ebi.ac.uk/biostudies/studies/S-EPMC4648709biostudies-literatureUnknown59(6)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.Molecular cellP16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma.PMC4648709R01 GM071872R01 HD082567R01 DK044838P50 HD012303T32 GM008666R01 EY018660P30EY022589R01EY023704P42 ES010337I01 BX001898P30 EY022589U54 HD012303R01 EY014448R01HG008135P30 DK063491P30 CA023100R01 EY014428R01 HD072754Flagg KWeinreb RNMellon PLZhang KCao GKrawczyk MZin CShi WZhang LKrupa MLiu YZhao LOuyang HPatel SZheng LJafari MWen CWang WLi GRosenfeld MGZhuo YLi OSkowronska-Krawczyk DAi MLuo HZhong ZSun XChen DChung CZhu JYeh ELuo JLin DShi CZhong SAbagyan RGao WXu Y58falseP16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma.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.2015-01-01T00:00:00Z2015 Sep2024-11-09T14:20:19.53Z2019-03-27T02:02:08ZS-EPMC46487092636538010.1016/j.molcel.2015.07.027