Fig. 2

Implication of the UPR pathways in the pathogenesis of glaucoma. Left panel: Mutations of MYOC gene and other factors induces ER stress resulting in activation of the PERK/ATF4/CHOP pathway. Activation of this pathway leads to increased reactive oxygen species (ROS), inflammation, and DNA damage, promoting TM cell apoptosis. In addition, ATF4 increases TM stiffness contributing to reduced outflow of aqueous humor and increased IOP. Right panel: ER stress is induced by multiple factors, including mutations of genes such as TMCO1 and OPTN, increased IOP, ischemia, and others, in retinal ganglion cells (RGCs) during glaucoma. Activation of XBP1 increases expressions of ER chaperones and neurotrophic factors, such as brain derived neurotrophic factor (BDNF), p58^IPK, and mesencephalic astrocyte-derived neurotrophic factor (MANF), reducing apoptosis of RGCs. Activation of ATF4/CHOP, mitochondrial dysfunction, and calcium dyshomeostasis, contribute to RGC cell death and degeneration