Histone Hyperacetylation Upregulates PKC{delta} in Dopaminergic Neurons to Induce Cell Death: Relevance to Epigenetic Mechanisms of Neurodegeneration in Parkinson’s Disease [Molecular Bases of Disease]

October 23rd, 2014 by Jin, H., Kanthasamy, A., Harischandra, D. S., Kondru, N., Ghosh, A., Panicker, N., Anantharam, V., Rana, A., Kanthasamy, A. G.

The oxidative stress-sensitive protein kinase Cδ (PKCδ) has been implicated in dopaminergic neuronal cell death. However, little is known about the epigenetic mechanisms regulating PKCδ expression in neurons. Here, we report a novel mechanism by which the PKCδ gene can be regulated by histone acetylation. Treatment with histone deacetylase inhibitor (HDACi) sodium butyrate (NaBu) induced PKCδ expression in cultured neurons, brain slices, and animal models. Several other HDACi also mimicked NaBu. The chromatin immunoprecipitation analysis revealed that hyperacetylation of histone H4 by NaBu is associated with the PKCδ promoter. Deletion analysis of PKCδ 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 PKCδ promoter activation. Cotransfection experiments and Sp inhibitors studies demonstrated that Sp1, Sp3 and Sp4 regulated NaBu-induced PKCδ upregulation. 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 p300/CBP potentiated the NaBu-mediated transactivation potential of Sp1/Sp3, whereas expressing several HDACs attenuated this effect, suggesting that p300/CBP and HDACs act as co-activators or co-repressors in histone acetylation-induced PKCδ upregulation. Finally, using genetic and pharmacological approaches, we showed that NaBu upregulation of PKCδ sensitizes neurons to cell death in a human dopaminergic cell model and brain slice cultures. Together, these results indicate that histone acetylation regulates PKCδ expression to augment nigrostriatal dopaminergic cell death, which could contribute to the progressive neuropathogenesis of Parkinson′s disease.
  • Posted in Journal of Biological Chemistry, Publications
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