Histone Hyperacetylation Up-regulates Protein Kinase Cδ in Dopaminergic Neurons to Induce Cell Death RELEVANCE TO EPIGENETIC MECHANISMS OF NEURODEGENERATION IN PARKINSON DISEASE

Background: Dysregulation of neuronal acetylation homeostasis promotes neurodegeneration. Results: Histone hyperacetylation up-regulates PKC in dopaminergic neurons and augments susceptibility to oxidative damage. Conclusion: Epigenetic regulation of PKC plays a proapoptotic role in neuronal cell death. Significance: The up-regulation of PKC expression by hyperacetylation provides an epigenetic molecular basis of neurodegenerative disease. The oxidative stress-sensitive protein kinase C (PKC) has been implicated in dopaminergic neuronal cell death. However, little is known about the epigenetic mechanisms regulating PKC expression in neurons. Here, we report a novel mechanism by which the PKC gene can be regulated by histone acetylation. Treatment with histone deacetylase (HDAC) inhibitor sodium butyrate (NaBu) induced PKC 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 PKC promoter. Deletion analysis of the PKC 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 PKC promoter activation. Cotransfection experiments and Sp inhibitor studies demonstrated that Sp1, Sp3, and Sp4 regulated NaBu-induced PKC 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 PKC up-regulation. Finally, using genetic and pharmacological approaches, we showed that NaBu up-regulation of PKC sensitizes neurons to cell death in a human dopaminergic cell model and brain slice cultures. Together, these results indicate that histone acetylation regulates PKC expression to augment nigrostriatal dopaminergic cell death, which could contribute to the progressive neuropathogenesis of Parkinson disease.