Virally delivered, constitutively active NFκB improves survival of injured retinal ganglion cells

Galina Dvoriantchikova, Steve Pappas, Xueting Luo, Marcio Ribeiro, Dagmara Danek, Daniel Pelaez, Kevin K. Park, Dmitry Ivanov

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

As axon damage and retinal ganglion cell (RGC) loss lead to blindness, therapies that increase RGC survival and axon regrowth have direct clinical relevance. Given that NFκB signaling is critical for neuronal survival and may regulate neurite growth, we investigated the therapeutic potential of NFκB signaling in RGC survival and axon regeneration. Although both NFκB subunits (p65 and p50) are present in RGCs, p65 exists in an inactive (unphosphorylated) state when RGCs are subjected to neurotoxic conditions. In this study, we used a phosphomimetic approach to generate DNA coding for an activated (phosphorylated) p65 (p65mut), then employed an adeno-associated virus serotype 2 (AAV2) to deliver the DNA into RGCs. We tested whether constitutive p65mut expression prevents death and facilitates neurite outgrowth in RGCs subjected to transient retinal ischemia or optic nerve crush (ONC), two models of neurotoxicity. Our data indicate that RGCs treated with AAV2-p65mut displayed a significant increase in survival compared to controls in ONC model (77 ± 7% vs. 25 ± 3%, P-value = 0.0001). We also found protective effect of modified p65 in RGCs of ischemic retinas (55 ± 12% vs. 35 ± 6%), but not to a statistically significant degree (P-value = 0.14). We did not detect a difference in axon regeneration between experimental and control animals after ONC. These findings suggest that increased NFκB signaling in RGCs attenuates retinal damage in animal models of neurodegeneration, but insignificantly impacts axon regeneration.

Original languageEnglish (US)
Pages (from-to)2935-2943
Number of pages9
JournalEuropean Journal of Neuroscience
Volume44
Issue number11
DOIs
StatePublished - Dec 1 2016

Keywords

  • adeno-associated virus serotype 2
  • optic nerve crush model
  • phosphomimetic
  • retinal ganglion cells
  • transient retinal ischemia model

ASJC Scopus subject areas

  • Neuroscience(all)

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