title: Excessive HDAC activation is critical for neurodegeneration in the rd1 mouse.
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.
authors.affiliation: Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Sancho-Pelluz
authors.forename: M V
authors.initials: MV
authors.lastname: Alavi
authors.forename: A
authors.initials: A
authors.lastname: Sahaboglu
authors.forename: S
authors.initials: S
authors.lastname: Kustermann
authors.forename: P
authors.initials: P
authors.lastname: Farinelli
authors.forename: S
authors.initials: S
authors.lastname: Azadi
authors.forename: T
authors.initials: T
authors.lastname: van Veen
authors.forename: F J
authors.initials: FJ
authors.lastname: Romero
authors.forename: F
authors.initials: F
authors.lastname: Paquet-Durand
authors.forename: P
authors.initials: P
authors.lastname: Ekström
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012162:Retinal Degeneration / Q000201:enzymology* / Q000473:pathology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D011065:Poly(ADP-ribose) Polymerases; D006655:Histone Deacetylases