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Runxia Wen, Ruanne Y J Lai, Colette Chiu, Beatrice M Tam, Orson L Moritz; HDAC inhibitors alter retinal degeneration phenotypes and induce autophagy in Xenopus laevis models of retinal degeneration.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2268.
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© ARVO (1962-2015); The Authors (2016-present)
Valproic acid (VPA) is a proposed treatment for retinitis pigmentosa. We previously determined that VPA can prevent retinal degeneration in P23H rhodopsin transgenic X. laevis, but promotes retinal degeneration in T17M rhodopsin transgenic X. laevis. To determine the origin of this effect, we assessed the ability of nine pharmacologically related compounds to replicate these effects. As VPA is known to induce autophagy in other cell types we also investigated whether autophagy was induced in rod photoreceptors treated with VPA and pharmacologically related compounds.
We exposed transgenic X. laevis tadpoles and their wildtype siblings to potentially therapeutic molecules in their aqueous environment from day 2 after fertilization to day 14 after fertilization, with drugs renewed daily. Tadpoles were sacrificed and one eye was used for dot blot analysis for total rhodopsin, while the contralateral eye was cryosectioned and analyzed by confocal microscopy.To examine the effects of drugs on photoreceptor ultrastructure, tadpoles were treated similarly, and sacrificed at day 6. Eyes were enucleated and processed for electron microscopy.
We determined that the beneficial effects of VPA for retinal degeneration associated with the P23H rhodopsin mutation were replicated by HDAC inhibitors, but not by other compounds such as carbamazepine. HDAC inhibitors, including sodium butyrate (NaBu) also consistently promoted retinal degeneration in T17M rhodopsin transgenic X. laevis. In wildtype retinas treated with both VPA and NaBu, electron micrographs showed increases in vesicular membranes, specifically double-membrane vesicles within rod inner segments, consistent with activation of the autophagy pathway in rod photoreceptors. Similar vesiculation also occurred in retinas expressing P23H rhodopsin.
HDAC inhibitors, including VPA and NaBu, prevent retinal degeneration in P23H rhodopsin transgenic X. laevis, but promote retinal degeneration in T17M rhodopsin transgenic X. laevis. HDAC inhibitors also promote autophagy in rod photoreceptors, and autophagy is associated with expression of P23H rhodopsin, likely representing an attempt to remove damaged ER or protein aggregates. Autophagy induced by HDAC inhibitors could be a potential mechanism by which VPA and NaBu rescue retinal degeneration associated with P23H rhodopsin.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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