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Open Access Publications from the University of California

P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma

  • Author(s): Skowronska-Krawczyk, D
  • Zhao, L
  • Zhao, L
  • Zhao, L
  • Zhu, J
  • Zhu, J
  • Weinreb, RN
  • Cao, G
  • Luo, J
  • Flagg, K
  • Patel, S
  • Wen, C
  • Krupa, M
  • Luo, H
  • Ouyang, H
  • Ouyang, H
  • Lin, D
  • Wang, W
  • Wang, W
  • Li, G
  • Xu, Y
  • Li, O
  • Li, O
  • Chung, C
  • Yeh, E
  • Jafari, M
  • Ai, M
  • Zhong, Z
  • Shi, W
  • Zheng, L
  • Krawczyk, M
  • Chen, D
  • Shi, C
  • Zin, C
  • Zhu, J
  • Mellon, PL
  • Gao, W
  • Abagyan, R
  • Zhang, L
  • Sun, X
  • Zhong, S
  • Zhuo, Y
  • Rosenfeld, MG
  • Liu, Y
  • Zhang, K
  • Zhang, K
  • Zhang, K
  • Zhang, K
  • Zhang, K
  • et al.

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© 2015 Elsevier Inc. 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-dependentkinase inhibitor 2A, isoform INK4a). Wefurther 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 inhuman 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. Zhang etal. report p16INK4a as a downstream integrator of diverse signals, such as inherited genetic risk, age, and intraocular pressure, in the pathogenesis of glaucoma. They demonstrate that upregulation of SIX6 upon stress directly increases p16INK4a, leading to retinal ganglion cell senescence and death.

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