Increased intraocular pressure alters the cellular distribution of HuR protein in retinal ganglion cells – A possible sign of endogenous neuroprotection failure

The Role of Endogenous Neuroprotective Mechanisms in the Prevention of Retinal Ganglion Cells Degeneration

“…From among the factors we described in this review, the human antigen R (HuR protein) seems to be the most promising endogenous target for experimental and translational therapy. In glaucoma, it has been shown that there are similar patterns of HuR protein alterations in both rat and human what allows to expect that effects of HuR-targeted therapies may have similar, thus translational outcomes ( Smedowski et al, 2018 ). HuR protein represent the pleiotropic factor that post-translationally regulates majority of described intracellular processes and molecules, especially antioxidant enzymes, growth factors, stress response factors, cell cycle regulating proteins and autophagy.…”

“…In healthy retinas MT I/II and III are expressed mostly in RGC axons (retinal nerve fiber layer) and the inner plexiform layer ( Suemori et al, 2006 ). Similarly, isoforms MT I and III have been detected in proteomic analyses of ON homogenates ( Smedowski et al, 2018 ). In stress conditions, expression of MT has been shown to increase within RNFL and RGC bodies, suggesting its role as an endogenous neuroprotective factor ( Suemori et al, 2006 ).…”

“…Relevant for our context, in vitro studies showed that HuR was activated by oxidative stress in TM cells ( Mochizuki et al, 2012 ). More recently, in vivo evidence by our group revealed that changes in HuR subcellular localization (i.e., nuclear-cytoplasmic shuttling) within RGCs occurred at early times after IOP induction in an animal model of glaucoma; these effects were followed at longer times by a progressive decrease of cytoplasmic HuR levels, including the expression of proteins essential for cell homeostasis (p53, Hsp70) and likely contributes to chronic IOP-induced RGC degeneration ( Smedowski et al, 2018 ). Similar alterations in HuR content and subcellular localization were found in human POAG samples, in support of the involvement of HuR in glaucoma ( Smedowski et al, 2018 ).…”

“…Interestingly, there are several known TNFα cross-interacting pathways, with described neuroprotective factors. ELAVL1/HuR protein regulates the expression of TNFα, as well as other pro- and anti-inflammatory cytokines, like IL-1, IL-6, IL-8, IL-10, participating in cellular homeostasis ( Smedowski et al, 2018 ). TNFα expression is also regulated by erythropoietin, however, the mechanism of this cross-pathway depends on the way of inflammatory process activation ( Hines-Beard et al, 2016 ).…”

Autophagy Stimulus Promotes Early HuR Protein Activation and p62/SQSTM1 Protein Synthesis in ARPE‐19 Cells by Triggering Erk1/2, p38MAPK, and JNK Kinase Pathways

“…For instance, a key role for Erk1/2, as well as AMPK, in AMD has been suggested [ 63 ]. Moreover, recent studies have confirmed the importance of HuR in various ocular pathologies [ 64 , 65 ] and laid the foundation for the druggability assessment of HuR protein [ 66 ]; compounds able to directly act on the HuR protein and p62 mRNA complex formation may thus represent new potential tools regulating p62 content.…”