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Dmitry V Ivanov, Galina Dvoriantchikova, Steve Pappas, Xueting Luo, Marcio Ribeiro, Dagmara Danek, Daniel Pelaez, Kevin Park; Constitutively Active Transcription Factor NFκB Facilitates Survival Of Damaged Retinal Ganglion Cells. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1164.
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© 2017 Association for Research in Vision and Ophthalmology.
Retinal ganglion cells (RGCs) are the only retinal neurons that send their axons to the visual cortex of the brain. Since axon damage and RGC loss (resulting from glaucoma, ischemic optic neuropathy, etc.) progressively lead to blindness, therapies designed to increase RGC survival and improve axon regrowth have direct clinical relevance. Given that NFκB signaling regulates neurite growth and is critical for neuronal survival in the central nervous system, we investigated the therapeutic potential of NFκB signaling in RGC survival and axon regeneration.
Although both subunits of NFκB (p65 and p50) are present in RGCs, p65 exists in an inactive (unphosphorylated) state when these neurons are subjected to neurotoxic conditions. Importantly, while phosphorylation of p65’s Ser276 residue facilitates NFκB-dependent pro-survival effects, phosphorylation of p65 on Ser536 can inhibit neurite regrowth. Since changing the Ser276 to a phosphomimetic Asp (S276D) can mimic p65 phosphorylation (activation), and since a Ser-to-Ala substitution at p65’s residue 536 (S536A) can prevent phosphorylation at this site, we generated DNA coding for a p65 S276DS536A double mutant (p65mut), then employed an adeno-associated virus serotype 2 (AAV2) vector to deliver the DNA directly into RGCs. Using a transient retinal ischemia model and an optic nerve crush model, we then tested whether constitutive expression of the p65mut protein prevents death and facilitates neurite outgrowth in RGCs subjected to these neurotoxic conditions.
Our data indicate that the modified protein p65mut was highly expressed (predominantly in the cell nucleus) in RGCs transduced with AAV2-p65mut viral particles. RGCs of animals injected with AAV2-p65mut displayed a significant increase in survival compared to controls injected with AAV2-mCherry in both the transient retinal ischemia model (60±12% vs. 33±6%) and the optic nerve crush model (77±7% vs. 25±3%). We did not detect a difference in axon regeneration between experimental and control animals after optic nerve crush.
Our findings suggest that increased activity of the NFκB signaling cascade in RGCs attenuates retinal damage in animal models of neurodegeneration. However, NFκB signaling activity in RGCs has a limited impact on axon regeneration, suggesting that NFκB-induced RGC survival is not sufficient to allow axon regeneration.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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