Rescue of Glaucomatous Neurodegeneration by Differentially Modulating Neuronal Endoplasmic Reticulum Stress Molecules

Abstract

Axon injury is an early event in neurodegenerative diseases that often leads to retrograde neuronal cell death and progressive permanent loss of vital neuronal functions. The connection of these two obviously sequential degenerative events, however, is elusive. Deciphering the upstream signals that trigger the neurodegeneration cascades in both neuronal soma and axon would be a key step toward developing the effective neuroprotectants that are greatly needed in the clinic. We showed previously that optic nerve injury-induced neuronal endoplasmic reticulum (ER) stress plays an important role in retinal ganglion cell (RGC) death. Using two in vivo mouse models of optic neuropathies (traumatic optic nerve injury and glaucoma) and adeno-associated virus-mediated RGC-specific gene targeting, we now show that differential manipulation of unfolded protein response pathways in opposite directions-inhibition of eukaryotic translation initiation factor 2␣-C/EBP homologous protein and activation of X-box binding protein 1-promotes both RGC axons and somata survival and preserves visual function. Our results indicate that axon injury-induced neuronal ER stress plays an important role in both axon degeneration and neuron soma death. Neuronal ER stress is therefore a promising therapeutic target for glaucoma and potentially other types of neurodegeneration.

Silicone Oil-Induced Ocular Hypertension in Mouse Models Glaucomatous Neurodegeneration and Neuroprotection

“…We previously showed that ER stress is induced by ON injury and that CHOP deletion in combination with XBP-1s overexpression synergistically promotes neuroprotection of RGC somata and axons in mouse ON crush model, microbead-induced glaucoma model and EAE/optic neuritis(29, 34, 35). These results suggested that these ER stress molecules are potential therapeutic targets for neuroprotection in optic neuropathies.…”

“…We therefore examined whether the SOHU model can be used to evaluate the effect of ER stress manipulation on glaucomatous RGCs and ON. We previously demonstrated that the microRNA-based AAV-CHOP shRNA-GFP knocks down endogenous CHOP in mouse retinas and increases RGC soma and axon survival in the ON crush model and microbeads-induced glaucoma model(29). We modified this AAV vector by replacing GFP with XBP-1s to knockdown CHOP and express XBP-1s with a single AAV vector.…”

“…However, the difficulty of retaining microbeads at the angle of anterior chamber and of controlling the degree of aqueous outflow blockade results in a low success rate and high variabilities in the magnitude of IOP elevation and neurodegeneration. Furthermore, its lengthy duration (6-12 weeks after microbeads injection) causes death of only 30% of RGC(26, 28, 29), leaving a narrow window for preclinical testing of neuroprotective therapies. It is therefore critically important to develop a simple but effective ocular hypertension model in mice that closely resembles human glaucoma, and that can be readily adapted to larger animals with minimal confounding factors.…”

“…Endoplasmic reticulum (ER) stress is a complex cascade of reactions that are activated when the ER, the organelle responsible for synthesis and proper folding of proteins, is overwhelmed by unfolded and misfolded proteins, a process that is called the unfolded protein response (UPR)(32, 33). We previously identified the important role of ER stress in glaucomatous neurodegeneration and demonstrated significant neuroprotection of RGC and ON by modulating ER stress molecules, C/EBP homologous protein (CHOP) and X-box binding protein 1 (XBP-1)(29, 34, 35). Here we apply an adeno-associated virus (AAV) that mediates CHOP inhibition and XBP-1 activation in a single vector to the SO-induced ocular hypertension model.…”

Major review: Molecular genetics of primary open-angle glaucoma

“…MYOC mutations reportedly affect the ER stress response, which has been implicated in the pathogenesis of glaucoma (Chrysostomou et al, 2013; Zode et al, 2012; Zode et al, 2011). ER stress pathways also appear to play a role in the pathogenesis of POAG in the retina based on mouse models of optic nerve injury or transgenic mutated myocilin (Carbone et al, 2011; Hu et al, 2012; Yang et al, 2016a; Zode et al, 2012; Zode et al, 2011). Mitochondrial-related pathways have also been implicated in POAG pathogenesis.…”