title: Combined HDAC1 and HDAC2 Depletion Promotes Retinal Ganglion Cell Survival After Injury Through Reduction of p53 Target Gene Expression.
abstract: Histones deacetylases (HDACs), besides their function as epigenetic regulators, deacetylate and critically regulate the activity of nonhistone targets. In particular, HDACs control partially the proapoptotic activity of p53 by balancing its acetylation state. HDAC inhibitors have revealed neuroprotective properties in different models, but the exact mechanisms of action remain poorly understood. We have generated a conditional knockout mouse model targeting retinal ganglion cells (RGCs) to investigate specifically the functional role of HDAC1 and HDAC2 in an acute model of optic nerve injury. Our results demonstrate that combined HDAC1 and HDAC2 ablation promotes survival of axotomized RGCs. Based on global gene expression analyses, we identified the p53-PUMA apoptosis-inducing axis to be strongly activated in axotomized mouse RGCs. Specific HDAC1/2 ablation inhibited this apoptotic pathway by impairing the crucial acetylation status of p53 and reducing PUMA expression, thereby contributing to the ensuing enhanced neuroprotection due to HDAC1/2 depletion. HDAC1/2 inhibition and the affected downstream signaling components emerge as specific targets for developing therapeutic strategies in neuroprotection.
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zürich, CH, Switzerland frederic.lebrun@biol.ethz.ch.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lebrun-Julien
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zürich, CH, Switzerland.
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
mesh_terms: D000107:Acetylation; D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D019771:Axotomy; D002470:Cell Survival / Q000502:physiology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D016158:Genes, p53; D056284:Histone Deacetylase 1 / Q000172:deficiency* / Q000235:genetics; D056464:Histone Deacetylase 2 / Q000172:deficiency* / Q000235:genetics; D020935:MAP Kinase Signaling System; D018345:Mice, Knockout; D000066829:Neuroprotection; D020221:Optic Nerve Injuries / Q000201:enzymology* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000201:enzymology* / Q000473:pathology / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C488588:PUMA protein, mouse; D025521:Tumor Suppressor Proteins; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2
keywords: axotomy; central nervous system; histones deacetylases; neuroprotection; p53; retinal ganglion cell