α-Synuclein Negatively Regulates Protein Kinase Cδ Expression to Suppress Apoptosis in Dopaminergic Neurons by Reducing p300 Histone Acetyltransferase Activity

We recently demonstrated that protein kinase C delta (FRC delta), an important member of the novel PKC family, is a key oxidative stress-sensitive kinase that can be activated by caspase-3-dependent proteolytic cleavage to induce dopaminergic neuronal cell death. We now report a novel association between alpha-synuclein (alpha syn), a protein associated with the pathogenesis of Parkinson's disease, and PRC delta, in which alpha syn negatively modulates the p300- and nuclear factor-kappa B (NF kappa B)-dependent transactivation to downregulate proapoptotic kinase PRC delta expression and thereby protects against apoptosis in dopaminergic neuronal cells. Stable expression of human wild-type alpha syn at physiological levels in dopaminergic neuronal cells resulted in an isoform-dependent transcriptional suppression of PKC delta expression without changes in the stability of mRNA and protein or DNA methylation. The reduction in PKC delta transcription was mediated, in part, through the suppression of constitutive NF kappa B activity targeted at two proximal PRC delta promoter kappa B sites. This occurred independently of NF kappa B/I kappa B alpha (inhibitor of kappa B alpha) nuclear translocation but was associated with decreased NF kappa B-p65 acetylation. Also, alpha syn reduced p300 levels and its HAT (histone acetyltransferase) activity, thereby contributing to diminished PKC delta transactivation. Importantly, reduced PKC delta and p300 expression also were observed within nigral dopaminergic neurons in alpha syn-transgenic mice. These findings expand the role of alpha syn in neuroprotection by modulating the expression of the key proapoptotic kinase PKC delta in dopaminergic neurons.