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Abstract #55693 Published in IGR 15-4
Down-regulation of the RNA editing enzyme ADAR2 contributes to RGC death in a mouse model of glaucoma
Wang AL; Carroll RC; Nawy SPLoS ONE 2014; 9: e91288
Glaucoma is a progressive neurodegenerative disease of retinal ganglion cells (RGCs) associated with characteristic axon degeneration in the optic nerve. Excitotoxic damage due to increased Ca(2+) influx, possibly through NMDA-type glutamate receptors, has been proposed to be a cause of RGC dysfunction and death in glaucoma. Recent work has found that expression of another potentially critical receptor, the Ca(2+)-permeable AMPA receptor (CP-AMPAR), is elevated during various pathological conditions (including ALS and ischemia), resulting in increased neuronal death. Here we test the hypothesis that CP-AMPARs contribute to RGC death due to elevated Ca(2+) influx in glaucoma. AMPA receptors are impermeable to Ca(2+) if the tetrameric receptor contains a GluA2 subunit that has undergone Q/R RNA editing at a site in the pore region. The activity of ADAR2, the enzyme responsible for this RNA editing, generally ensures that the vast majority of GluA2 proteins are edited. Here, we demonstrate that ADAR2 levels decrease in a mouse model of glaucoma in which IOP is chronically elevated. Furthermore, using an in vitro model of RGCs, we find that knockdown of ADAR2 using siRNA increased the accumulation of Co(2+) in response to glutamate, and decreased the rectification index of AMPA currents detected electrophysiologically, indicating an increased Ca(2+) permeability through AMPARs. The RGCs in primary culture also exhibited increased excitotoxic cell death following knock down of ADAR2. Furthermore, cell death was reversed by NASPM, a specific blocker for CP-AMPARs. Together, our data suggest that chronically elevated IOP in adult mice reduces expression of the ADAR2 enzyme, and the loss of ADAR2 editing and subsequent disruption of GluA2 RNA editing might potentially play a role in promoting RGC neuronal death as observed in glaucoma.
Full article
Classification:
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
11.8 Neuroprotection (Part of: 11 Medical treatment)
3.5 Molecular biology incl. SiRNA (Part of: 3 Laboratory methods)
3.8 Pharmacology (Part of: 3 Laboratory methods)
