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Virally delivered, constitutively active NF κB improves survival of injured retinal ganglion cells
Author(s) -
Dvoriantchikova Galina,
Pappas Steve,
Luo Xueting,
Ribeiro Marcio,
Danek Dagmara,
Pelaez Daniel,
Park Kevin K.,
Ivanov Dmitry
Publication year - 2016
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.13383
Subject(s) - retinal ganglion cell , axon , neurite , neurodegeneration , biology , retina , microbiology and biotechnology , retinal , nf κb , signal transduction , neuroscience , pathology , medicine , biochemistry , disease , in vitro
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 NF κB signaling is critical for neuronal survival and may regulate neurite growth, we investigated the therapeutic potential of NF κB signaling in RGC survival and axon regeneration. Although both NF κB subunits (p65 and p50) are present in RGC s, p65 exists in an inactive (unphosphorylated) state when RGC s 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 ( AAV 2) to deliver the DNA into RGC s. We tested whether constitutive p65mut expression prevents death and facilitates neurite outgrowth in RGC s subjected to transient retinal ischemia or optic nerve crush ( ONC ), two models of neurotoxicity. Our data indicate that RGC s treated with AAV 2‐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 RGC s 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 NF κB signaling in RGC s attenuates retinal damage in animal models of neurodegeneration, but insignificantly impacts axon regeneration.