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Z. Yang, Y. Ge, M. Pease, H. Quigley, D. J. Zack; Role of Endoplasmic Reticulum Stress in Retinal Ganglion Cell Death in Glaucoma and Optic Nerve Injury. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5812.
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We have been investigating the mechanism of RGC death in glaucoma and various optic neuropathies by applying a variety of bioinformatic and molecular biology approaches. Based upon the pattern of gene expression changes following optic nerve injury, we sought to elucidate the role of excessive unfolded protein response (UPR) and endoplasmic reticulum (ER) stress in the pathogenesis of RGC death secondary to optic nerve injury.
We employed microarray approach to profile the gene expression alterations in rat model of glaucoma and optic nerve transection, and found upregulation of a panel of genes associated with activated UPR and ER stress. Immunohisotochemistry was used to assess the upregulation of CHOP, a bZIP transcription factor and marker for unmitigated ER stress, following experimental intraocular pressure (IOP) elevation and traumatic optic nerve injury. Glutamate excitotoxicity and optic nerve crush in mice were utilized to assess whether Chop deletion can offer protection to injured RGCs.
We observed a rapid and significant activation of ER stress in RGCs prior to their death in a rat glaucoma model, and following optic nerve transection and pharmacological disruption of RGC axonal transport. In addition, in cultured primary mouse RGCs, we identified the upregulation of a number of UPR-related genes, and this upregulation is reduced by treatment with a neuroprotective protein kinase inhibitor. Moreover, genetic deletion of a death-inducing gene associated with ER stress signaling can improve RGC survival following optic nerve injury (44.7 ± 4.8% in wildtype vs. 81.1 ± 19.5% in Chop -/- mice, n = 6, P < 0.002) and after glutamate induced excitotoxicity.
Our results suggest that excessive UPR and ER stress may contribute significantly to the upstream events that ultimately lead to RGC death in glaucoma and after optic nerve injury. Modulation of UPR/ER stress mechanisms may provide a novel therapeutic option for the treatment of glaucoma and other optic neuropathies.
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