RNA‐binding protein ELAVL1‐mediated neuroprotection of retinal ganglion cells

Abstract

Aims/Purpose: To evaluate the impact of ELAVL1 overexpression on survival and function of retinal ganglion cells (RGC) in rat glaucoma model.Methods: The study included ex vivo and in vivo approaches. Ex vivo, we used rat retinal explants to investigate, whether AAV‐ELAVL1 delivery affects the survival of RGC in the degeneration model induced by axotomy. In vivo approach investigated histology and function of RGC in rat glaucoma model. Rats received intravitreal injection of AAV‐ELAVL1, AAV‐ELAVL1(S202A) or AAV‐control. To induce chronic glaucoma, unilateral episcleral vein cauterization was performed. Animals underwent electroretinography tests (ERG) during the experiment. Collected retinas and optic nerves were processed for immunostainings, western blots, and stereology.Results: In ex vivo retinal explants culture, the RGC count was 162 ± 35, 148 ± 22 and 149 ± 28 for AAV‐ELAVL1, AAV‐ELAVL1(S202A) and control, respectively (p < 0.03). The IOP values were similar in all experimental groups, and on average, they were significantly higher than in healthy eyes (p < 0.001). In retinal histology, clear neuroprotective effect in the AAV‐ELAVL1 group was observed. After AAV therapy, both constructs (ELAVL1 and ELAVL1(S202A) showed a significant increase in protein expression in RGC, which was also associated with a significant increase in the expression of BDNF in the retinas, especially after AAV‐ELAVL1 treatment. In functional tests, the PhNR response was significantly reduced in AAV‐control glaucoma (p < 0.001). The application of AAV‐ELAVL1 treatment resulted in the preservation of RGC function at a level very similar to the situation before the induction of glaucoma.Conclusions: The AAV‐ELAVL1 approach showed a very strong neuroprotective effect in a rat glaucoma model. The neuroprotective effect is associated with antioxidant and anti‐inflammatory activity with the increase in BDNF expression, which intensifies the neuroprotective effect.