Abstract
Inherited retinal degenerations, collectively termed retinitis pigmentosa (RP), constitute one of the leading causes of blindness in the developed world. RP is at present untreatable and the underlying neurodegenerative mechanisms are unknown, even though the genetic causes are often established. Acetylation and deacetylation of histones, carried out by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively, affects cellular division, differentiation, death and survival. We found acetylation of histones and probably other proteins to be dramatically reduced in degenerating photoreceptors in the rd1 human homologous mouse model for RP. Using a custom developed in situ HDAC activity assay, we show that overactivation of HDAC classes I/II temporally precedes photoreceptor degeneration. Moreover, pharmacological inhibition of HDACs I/II activity in rd1 organotypic retinal explants decreased activity of poly-ADP-ribose-polymerase and strongly reduced photoreceptor cell death. These findings highlight the importance of protein acetylation for photoreceptor cell death and survival and propose certain HDAC classes as novel targets for the pharmacological intervention in RP.
Highlights
Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases that result in selective cell death of retinal photoreceptors
Western blot (WB) of P11 in vivo retinae with the acetyl-lysine Ab (Figure 2g) mainly revealed bands between 12 and 17 kDa that corresponded to the reported molecular weights of different histones and showed numerically decreased acetylation levels in the rd[1] retina
We show that histone deacetylase (HDAC) activity was causally related to inherited photoreceptor cell death in the rd[1] mouse and that this detrimental effect was tied to HDACs I/II
Summary
Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases that result in selective cell death of retinal photoreceptors. At least 40 RP causing mutations have been identified so far, but the metabolic pathways leading to photoreceptor cell death have not been resolved, and no adequate RP treatment is available.[1]. The rd[1] mouse is one of the most studied human homologous RP animal models and carries a loss-of-function mutation in the gene encoding for the b-subunit of rod photoreceptor cGMP phosphodiesterase-6.2 This leads to an accumulation of cGMP, which eventually causes photoreceptor cell death.[3,4] In microarray experiments, we and others found rd[1] degeneration to be accompanied by extensive changes in gene expression.[5,6,7] some changes may result from direct and specific effects of cGMP on defined genes,[8] it is likely that more generalized alterations of the transcriptional machinery are involved.
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