Histone deacetylase 3 HDAC3 plays an important role in retinal ganglion cell death after acute optic nerve injuryReportar como inadecuado




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Molecular Neurodegeneration

, 9:39

First Online: 28 September 2014Received: 27 May 2014Accepted: 22 September 2014

Abstract

BackgroundOptic nerve damage initiates a series of early atrophic events in retinal ganglion cells RGCs that precede the BAX-dependent committed step of the intrinsic apoptotic program. Nuclear atrophy, including global histone deacetylation, heterochromatin formation, shrinkage and collapse of nuclear structure, and the silencing of normal gene expression, comprise an important obstacle to overcome in therapeutic approaches to preserve neuronal function. Several studies have implicated histone deacetylases HDACs in the early stages of neuronal cell death, including RGCs. Importantly, these neurons exhibit nuclear translocation of HDAC3 shortly after optic nerve damage. Additionally, HDAC3 activity has been reported to be selectively toxic to neurons.

ResultsRGC-specific conditional knockout of Hdac3 was achieved by transducing the RGCs of Hdac3 mice with an adeno-associated virus serotype 2 carrying CRE recombinase and GFP AAV2-Cre-GFP. Controls included similar viral transduction of Rosa26 reporter mice. Optic nerve crush ONC was then performed on eyes. The ablation of Hdac3 in RGCs resulted in significant amelioration of characteristics of ONC-induced nuclear atrophy such as H4 deacetylation, heterochromatin formation, and the loss of nuclear structure. RGC death was also significantly reduced. Interestingly, loss of Hdac3 expression did not lead to protection against RGC-specific gene silencing after ONC, although this effect was achieved using the broad spectrum inhibitor, Trichostatin A.

ConclusionAlthough other HDACs may be responsible for gene expression changes in RGCs, our results indicate a critical role for HDAC3 in nuclear atrophy in RGC apoptosis following axonal injury. This study provides a framework for studying the roles of other prevalent retinal HDACs in neuronal death as a result of axonal injury.

KeywordsHDAC Epigenetics Retinal ganglion cell Neuronal degeneration Apoptosis Chromatin remodeling Deacetylation Heterochromatin AbbreviationsONCOptic nerve crush

RGCRetinal ganglion cell

GCLGanglion cell layer

INLInner nuclear layer

IPLInner plexiform layer

ONLOuter nuclear layer

HDACHistone deacetylase

AcH4Acetylated histone 4

TEMTransmittance electron microscopy

βGeoβ-Galactosidase and neomycin phosphotransferase fusion reporter protein

X-galBCIG for 5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside

TSATrichostatin A

VPAValproic acid

PBSPhosphate-buffered saline

BSABovine serum albumin

DMSODimethyl sulfoxide

DAPI4’, 6-diamidino-2-phenylindole

cKOConditional knockout

AAV2-Cre-GFPAdeno-associated virus serotype 2 carrying Cre recombinase and green fluorescent protein

PGK-neoPhosphoglycerate kinase I neomycin resistance gene

gcGenome copies

NNucleus

nNucleolus

neNuclear envelope

mMüller endfoot

hcHeterochromatin

WTWild-type.

Electronic supplementary materialThe online version of this article doi:10.1186-1750-1326-9-39 contains supplementary material, which is available to authorized users.

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Autor: Heather M Schmitt - Heather R Pelzel - Cassandra L Schlamp - Robert W Nickells

Fuente: https://link.springer.com/



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