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ASN Neuro. 2015 Jun 30;7(3). pii: 1759091415593066. doi: 10.1177/1759091415593066. Print 2015 May-Jun.

Combined HDAC1 and HDAC2 Depletion Promotes Retinal Ganglion Cell Survival After Injury Through Reduction of p53 Target Gene Expression.

Author information

1
Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zürich, CH, Switzerland frederic.lebrun@biol.ethz.ch.
2
Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zürich, CH, Switzerland.

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.

KEYWORDS:

axotomy; central nervous system; histones deacetylases; neuroprotection; p53; retinal ganglion cell

PMID:
26129908
PMCID:
PMC4720215
DOI:
10.1177/1759091415593066
[Indexed for MEDLINE]
Free PMC Article

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