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.
Highlights
Blinding conditions, such as retinitis pigmentosa (RP), agerelated macular degeneration and cone dystrophies (COD), are characterized by the progressive loss of photoreceptors
To investigate whether HDAC6 transcript and protein is present in these cells, and to verify its constitutive expression in the mouse retina, lysates from wild-type C57BL/6J mouse retinae and 661W cells were subjected to immunoblot analysis or reverse transcription polymerase chain reaction (RT-PCR)
To study whether HDAC6 is active in 661W cells and that cells react to its inhibition, cells were incubated with tubastatin A (TST) for 24 h and hyperacetylation of α-tubulin was assessed by immunoblot procedures and indirect immunofluorescence
Summary
Blinding conditions, such as retinitis pigmentosa (RP), agerelated macular degeneration and cone dystrophies (COD), are characterized by the progressive loss of photoreceptors. Since cone photoreceptors have a high metabolic demand and are characterized by a high content of unsaturated lipids, they are susceptible to ROS-induced cell damage.[4,5] Increasing evidence obtained from animal RP models as well as from analyses of aqueous humor from RP patients suggests that oxidative stress contributes to secondary cone death in RP pathogenesis.[6,7] a variety of studies implicate that the application of antioxidants slows photoreceptor degeneration and promotes long-term survival of cones in mouse models of RP.[8,9,10]. Induction may prevent photoreceptor cell death in rodent models of RP.[16] Ischemic insults, oxidative stress and other factors induce the small heat-shock protein 27 HspB1) in retinal cells, providing neuroprotection due to its molecular chaperone activity, interaction with the cytoskeleton and prevention of apoptotic cell death.[17]
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