PUBLICATION
HDAC6 inhibition by tubastatin A is protective against oxidative stress in a photoreceptor cell line and restores visual function in a zebrafish model of inherited blindness
- Authors
- Leyk, J., Daly, C., Janssen-Bienhold, U., Kennedy, B.N., Richter-Landsberg, C.
- ID
- ZDB-PUB-171020-5
- Date
- 2017
- Source
- Cell Death & Disease 8: e3028 (Journal)
- Registered Authors
- Kennedy, Breandan N.
- Keywords
- none
- Datasets
- GEO:GSE86155
- MeSH Terms
-
- Heat-Shock Proteins/genetics
- Heat-Shock Proteins/metabolism
- Hydrogen Peroxide/antagonists & inhibitors*
- Hydrogen Peroxide/pharmacology
- Disease Models, Animal
- Hydroxamic Acids/pharmacology*
- Cell Survival
- Cell Line
- Gene Expression Regulation
- Signal Transduction
- Retinal Cone Photoreceptor Cells/drug effects
- Retinal Cone Photoreceptor Cells/metabolism
- Retinal Cone Photoreceptor Cells/pathology
- Leber Congenital Amaurosis/drug therapy*
- Leber Congenital Amaurosis/genetics
- Leber Congenital Amaurosis/metabolism
- Leber Congenital Amaurosis/pathology
- Tubulin/genetics*
- Tubulin/metabolism
- Histone Deacetylase 6/antagonists & inhibitors
- Histone Deacetylase 6/genetics*
- Histone Deacetylase 6/metabolism
- Reactive Oxygen Species/antagonists & inhibitors
- Reactive Oxygen Species/metabolism
- Acetylation
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism
- Histone Deacetylase Inhibitors/pharmacology*
- Animals
- Zebrafish
- HSP70 Heat-Shock Proteins/genetics
- HSP70 Heat-Shock Proteins/metabolism
- Mice
- Indoles/pharmacology*
- Humans
- PubMed
- 29048427 Full text @ Cell Death Dis.
Citation
Leyk, J., Daly, C., Janssen-Bienhold, U., Kennedy, B.N., Richter-Landsberg, C. (2017) HDAC6 inhibition by tubastatin A is protective against oxidative stress in a photoreceptor cell line and restores visual function in a zebrafish model of inherited blindness. Cell Death & Disease. 8:e3028.
Abstract
Retinal diseases, such as hereditary retinitis pigmentosa and age-related macular degeneration, are characterized by the progressive loss of photoreceptors. Histone deacetylase 6 (HDAC6) is considered as a stress surveillance factor and a potential target for neuroprotection and regeneration. Overexpression of HDAC6 has been connected to neurodegenerative disorders, and its suppression may provide protection. Here we show that HDAC6 is constitutively present in the mouse retina, and in the cone-like mouse cell line 661W. In 661W cells HDAC6 inhibition by the specific inhibitor tubastatin A (TST) led to the acetylation of α-tubulin, which is a major substrate for HDAC6. After oxidative stress, exerted by hydrogen peroxide, TST promoted cell survival and the upregulation of heat-shock proteins HSP70 and HSP25 by activation of heat-shock transcription factor 1. Furthermore, in response to oxidative stress the redox regulatory protein peroxiredoxin 1 (Prx1) was modulated in 661W cells by HDAC6 inhibition. The peroxide reducing activity of Prx1 is dependent on its acetylation, which is mediated by HDAC6. Pre-incubation with TST prevented the inactivation of Prx1 and its preserved activity may exert protective effects in photoreceptor cells. To determine whether TST treatment has a therapeutic effect on visual function, the dyeucd6 zebrafish model of inherited sight loss was utilized. Zebrafish have developed as a suitable model system for pharmacological testing. In vivo application of TST caused the hyperacetylation of α-tubulin, indicating that HDAC6 is active in this model. Furthermore, TST was sufficient to rescue visual function and retinal morphology. Hence, HDAC6 inhibition and the regulation of peroxiredoxin activity may play a significant role in protecting retinal cells and in particular photoreceptors, which are exposed to high levels of reactive oxygen species derived from oxidative stress-induced injuries.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping