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Liu Yang, Linqing Miao, Shaohua Li, Feisi Liang, Haoliang Huang, Xiuyin Teng, Kenneth S Shindler, Yang Hu; Morphology and function protection of RGC soma and axon by ER stress manipulation. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4954.
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© ARVO (1962-2015); The Authors (2016-present)
Loss of retinal ganglion cells (RGCs) and degeneration of optic nerve (ON) account for visual function deficits in optic neuropathies, such as traumatic ON injury, glaucoma and autoimmune optic neuritis. We previously demonstrated that both ON crush and glaucoma induce endoplasmic reticulum (ER) stress in RGCs and that RGC survival could be promoted by manipulating two key downstream molecules of ER stress in opposite ways: a) deletion of CCAAT/enhancer binding protein homologous protein (CHOP), and/or b) activation of X-box binding protein 1 (XBP-1). Here we tested the hypothesis that ER stress manipulation preserves visual function by preventing both RGC soma and axon (ON) degeneration.
Using three mouse ON injury models acute ON crush, microbeads injection-induced chronic glaucoma and myelin oligodendrocyte glycoprotein (MOG)-induced autoimmune optic neuritis in C57/B6 mice with or without CHOP inhibition and XBP-1 activation, we evaluated RGC survival in retina whole-mounts, axon degeneration in semithin cross-sections of ON and physiological function with visual evoked potential (VEP).
Whereas wild type (WT) mice showed 32% axon survival 5 days after ON crush, CHOP deletion plus AAV-XBP-1s expression increased axon survival to 58% (n = 8-10, p < 0.01). Results in the glaucoma model further confirmed the axon-protective effect: mice with same treatment showed 95% axon survival 8 weeks after microbeads injection and intraocular pressure elevation, whereas WT mice showed 71% axon survival (n = 8-10, p < 0.05). Consistent with the morphology results, VEP studies in the glaucoma model showed significantly shorter N1 and P1 latencies and larger N1-P1 amplitude in mice with CHOP deletion plus AAV-XBP-1s injection compared to WT mice. We finally confirmed the neuroprotection effect of ER stress manipulation in MOG-induced optic neuritis: RGC survival increased from 49% to 77% and axon survival increased from 40% to 63% 8 weeks after MOG injection (n = 8-10, p < 0.01). VEP studies, however, showed a significant difference in N1 and P1 latencies between treated group and control group at 5 weeks after MOG injection.
ER stress manipulation promotes significant RGC soma and axon survival and preserves visual function after acute and chronic ON injuries, indicating that ER stress is a promising common therapeutic target for neuroprotection.
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