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Induction of DARPP-32 by brain-derived neurotrophic factor in striatal neurons in vitro is modified by histone deacetylase inhibitors and Nab2.
- Source :
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PloS one [PLoS One] 2013 Oct 21; Vol. 8 (10), pp. e76842. Date of Electronic Publication: 2013 Oct 21 (Print Publication: 2013). - Publication Year :
- 2013
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Abstract
- Neurotrophins and modifiers of chromatin acetylation and deacetylation participate in regulation of transcription during neuronal maturation and maintenance. The striatal medium spiny neuron is supported by cortically-derived brain derived neurotrophic factor and is the most vulnerable neuron in Huntington's disease, in which growth factor and histone deacetylase activity are both disrupted. We examined the ability of three histone deacetylase inhibitors, trichostatin A, valproic acid and Compound 4 b, alone and combined with brain derived neurotrophic factor (BDNF), to promote phenotypic maturation of striatal medium spiny neurons in vitro. Exposure of these neurons to each of the three compounds led to an increase in overall histone H3 and H4 acetylation, dopamine and cyclic AMP-regulated phosphoprotein, 32 kDa (DARPP-32) mRNA and protein, and mRNA levels of other markers of medium spiny neuron maturation. We were, however, unable to prove that HDAC inhibitors directly lead to remodeling of Ppp1r1b chromatin. In addition, induction of DARPP-32 by brain-derived neurotrophic factor was inhibited by histone deacetylase inhibitors. Although BDNF-induced increases in pTrkB, pAkt, pERK and Egr-1 were unchanged by combined application with VPA, the increase in DARPP-32 was relatively diminished. Strikingly, the NGF1A-binding protein, Nab2, was induced by BDNF, but not in the presence of VPA or TSA. Gel shift analysis showed that α-Nab2 super-shifted a band that is more prominent with extract derived from BDNF-treated neurons than with extracts from cultures treated with VPA alone or VPA plus BDNF. In addition, overexpression of Nab2 induced DARPP-32. We conclude that histone deacetylase inhibitors inhibit the induction of Nab2 by BDNF, and thereby the relative induction of DARPP-32.
- Subjects :
- Acetylation drug effects
Animals
Blotting, Western
Calbindins genetics
Calbindins metabolism
Cell Differentiation drug effects
Cell Differentiation genetics
Cells, Cultured
Corpus Striatum cytology
Corpus Striatum drug effects
Corpus Striatum metabolism
Dopamine and cAMP-Regulated Phosphoprotein 32 genetics
Extracellular Signal-Regulated MAP Kinases metabolism
Histones metabolism
Hydroxamic Acids pharmacology
Mice
NIH 3T3 Cells
Neoplasm Proteins genetics
Neurons metabolism
Phosphorylation drug effects
Proto-Oncogene Proteins c-akt metabolism
Receptor, trkB metabolism
Repressor Proteins genetics
Reverse Transcriptase Polymerase Chain Reaction
Tumor Suppressor Proteins genetics
Tumor Suppressor Proteins metabolism
Valproic Acid pharmacology
Brain-Derived Neurotrophic Factor pharmacology
Dopamine and cAMP-Regulated Phosphoprotein 32 metabolism
Histone Deacetylase Inhibitors pharmacology
Neoplasm Proteins metabolism
Neurons drug effects
Repressor Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 24204683
- Full Text :
- https://doi.org/10.1371/journal.pone.0076842