Journal
MOLECULAR CELL
Volume 59, Issue 6, Pages 931-940Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2015.07.027
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Funding
- 973 Program [2015CB94600, 2013CB967504]
- State Key Laboratory of Ophthalmology
- NIH, Research to Prevent Blindness [RO1HG008135, R01EY023704, R01 HD072754, P30EY022589]
- European Molecular Biology Organization Long-Term Fellowship
- Swiss National Science Foundation
- San Diego Foundation
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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.
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