Purchase this article with an account.
Conor Daly, Lisa Shine, Eugene Dillon, Theresa Heffernan, Alison Reynolds, David Duffy, Gerard Cagney, Breandan N Kennedy; PHARMACOLOGICAL RESTORATION OF VISUAL FUNCTION IN A BLIND ZEBRAFISH MUTANT FOLLOWING HDAC INHIBITOR (HDACi) TREATMENT.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3617.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Controversially, pharmacological inhibition of Histone Deacetylase (HDAC) proteins is in clinical trial for the treatment of inherited retinal degenerations. Previous studies report that patients suffering from the inherited retinal degeneration Retinitis Pigmentosa (RP) may show improved visual field and acuity following treatment with the HDAC inhibitor valproic acid (VPA). Utilising zebrafish models of retinal degeneration we sought to rescue retinal morphology and visual function of a blind zebrafish mutant (dye mutant) by treatment with the HDACi Trichostatin A (TSA).
Visual function was assessed by Optokinetic Response (OKR) and Visual Motor Response (VMR) assays. Cone photoreceptor outer segment (OS) morphology, cilliary marginal zone (CMZ) apoptosis and cone photoreceptor outer segment (OS) length were assessed by light microscopy or transmission electron microscopy. Larvae were drug treated with HDACi (1 µM TSA, 10 µM MC1568 and 10 µM MS275) with or without 100-500 nM ANA-12 from 3-5 dpf at 28.5 C. Expression levels of candidate genes mediating dye rescue were analysed by quantitative real-time PCR. An unbiased shotgun proteomic analysis of TSA-treated dye eyes was carried out by LC-MS/MS and the resulting dataset analysed using Ingenuity Pathway Analysis (IPA).
The dye mutant has reduced visual behaviour and pronounced defects in retinal morphology compared to unaffected siblings. HDACi treatment of dye results in significantly improved vision, rescue of eye morphological defects, an 80% decrease in number of dead cells in CMZ and an increase in cone photoreceptor OS length. Proteins exhibiting significant differential expression in treated samples include phototransduction proteins Gnat2, Pde6c, and Gc3. The candidate gene bdnf showed increased transcription following HDAC inhibition and the Bdnf/Trkb signalling inhibitor, ANA-12, blocked HDACi meditaed dye rescue.
HDAC inhibition via the class I/II inhibitor Trichostatin A is effective in restoring visual function and rescuing morphological defects in a zebrafish model of retinal degeneration.
This PDF is available to Subscribers Only