September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Constitutively Active Transcription Factor NFκB Facilitates Survival Of Damaged Retinal Ganglion Cells
Author Affiliations & Notes
  • Dmitry V Ivanov
    Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States
    Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Galina Dvoriantchikova
    Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Steve Pappas
    Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Xueting Luo
    Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Marcio Ribeiro
    Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Dagmara Danek
    Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Daniel Pelaez
    Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida, United States
    Department of Biomedical Engineering, University of Miami, Miami, Florida, United States
  • Kevin Park
    Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Footnotes
    Commercial Relationships   Dmitry Ivanov, None; Galina Dvoriantchikova, None; Steve Pappas, None; Xueting Luo, None; Marcio Ribeiro, None; Dagmara Danek, None; Daniel Pelaez, None; Kevin Park, None
  • Footnotes
    Support  NIH Grant R01 EY022348, NIH Center Grant P30 EY014801
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 1164. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      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.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose : 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.

Methods : 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.

Results : 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.

Conclusions : 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.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×