Histone hyperacetylation up-regulates protein kinase Cdelta in dopaminergic neurons to induce cell death: relevance to epigenetic mechanisms of neurodegeneration in Parkinson disease Journal Article

Local Library Link: Find It @ Loyola

Authors: Jin, H.; Kanthasamy, A.; Harischandra, D. S.; Kondru, N.; Ghosh, A.; Panicker, N.; Anantharam, V.; Rana, A.; Kanthasamy, A. G.
Article Title: Histone hyperacetylation up-regulates protein kinase Cdelta in dopaminergic neurons to induce cell death: relevance to epigenetic mechanisms of neurodegeneration in Parkinson disease
Abstract: The oxidative stress-sensitive protein kinase Cdelta (PKCdelta) has been implicated in dopaminergic neuronal cell death. However, little is known about the epigenetic mechanisms regulating PKCdelta expression in neurons. Here, we report a novel mechanism by which the PKCdelta gene can be regulated by histone acetylation. Treatment with histone deacetylase (HDAC) inhibitor sodium butyrate (NaBu) induced PKCdelta expression in cultured neurons, brain slices, and animal models. Several other HDAC inhibitors also mimicked NaBu. The chromatin immunoprecipitation analysis revealed that hyperacetylation of histone H4 by NaBu is associated with the PKCdelta promoter. Deletion analysis of the PKCdelta promoter mapped the NaBu-responsive element to an 81-bp minimal promoter region. Detailed mutagenesis studies within this region revealed that four GC boxes conferred hyperacetylation-induced PKCdelta promoter activation. Cotransfection experiments and Sp inhibitor studies demonstrated that Sp1, Sp3, and Sp4 regulated NaBu-induced PKCdelta up-regulation. However, NaBu did not alter the DNA binding activities of Sp proteins or their expression. Interestingly, a one-hybrid analysis revealed that NaBu enhanced transcriptional activity of Sp1/Sp3. Overexpression of the p300/cAMP-response element-binding protein-binding protein (CBP) potentiated the NaBu-mediated transactivation potential of Sp1/Sp3, but expressing several HDACs attenuated this effect, suggesting that p300/CBP and HDACs act as coactivators or corepressors in histone acetylation-induced PKCdelta up-regulation. Finally, using genetic and pharmacological approaches, we showed that NaBu up-regulation of PKCdelta sensitizes neurons to cell death in a human dopaminergic cell model and brain slice cultures. Together, these results indicate that histone acetylation regulates PKCdelta expression to augment nigrostriatal dopaminergic cell death, which could contribute to the progressive neuropathogenesis of Parkinson disease.
Journal Title: The Journal of biological chemistry
Volume: 289
Issue: 50
ISSN: 1083-351X; 0021-9258
Publisher: by The American Society for Biochemistry and Molecular Biology, Inc  
Journal Place: United States
Date Published: 2014
Start Page: 34743
End Page: 34767
Language: eng
DOI/URL:

10.1074/jbc.M114.576702
Notes: LR: 20150401; CI: (c) 2014; GR: GM055835/GM/NIGMS NIH HHS/United States; GR: NS65167/NS/NINDS NIH HHS/United States; GR: R01 ES010586/ES/NIEHS NIH HHS/United States; GR: R01 ES10586/ES/NIEHS NIH HHS/United States; GR: R01 GM055835/GM/NIGMS NIH HHS/United States; GR: R01 NS065167/NS/NINDS NIH HHS/United States; GR: R01 NS074443/NS/NINDS NIH HHS/United States; GR: R01 NS074443/NS/NINDS NIH HHS/United States; JID: 2985121R; 0 (Histone Deacetylase Inhibitors); 0 (Histones); 0 (RNA, Messenger); 0 (Sp Transcription Factors); 107-92-6 (Butyric Acid); EC 2.3.1.48 (p300-CBP Transcription Factors); EC 2.7.11.13 (Protein Kinase C-delta); OID: NLM: PMC4263877 [Available on 12/12/15]; OTO: NOTNLM; PMCR: 2015/12/12 00:00; 2014/10/23 [aheadofprint]; ppublish