?-Synuclein negatively regulates protein kinase C? expression to suppress apoptosis in dopaminergic neurons by reducing p300 histone acetyltransferase activity.

ABSTRACT: We recently demonstrated that protein kinase C? (PKC?), 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 ?-synuclein (?syn), a protein associated with the pathogenesis of Parkinson's disease, and PKC?, in which ?syn negatively modulates the p300- and nuclear factor-?B (NF?B)-dependent transactivation to downregulate proapoptotic kinase PKC? expression and thereby protects against apoptosis in dopaminergic neuronal cells. Stable expression of human wild-type ?syn at physiological levels in dopaminergic neuronal cells resulted in an isoform-dependent transcriptional suppression of PKC? expression without changes in the stability of mRNA and protein or DNA methylation. The reduction in PKC? transcription was mediated, in part, through the suppression of constitutive NF?B activity targeted at two proximal PKC? promoter ?B sites. This occurred independently of NF?B/I?B? (inhibitor of ?B?) nuclear translocation but was associated with decreased NF?B-p65 acetylation. Also, ?syn reduced p300 levels and its HAT (histone acetyltransferase) activity, thereby contributing to diminished PKC? transactivation. Importantly, reduced PKC? and p300 expression also were observed within nigral dopaminergic neurons in ?syn-transgenic mice. These findings expand the role of ?syn in neuroprotection by modulating the expression of the key proapoptotic kinase PKC? in dopaminergic neurons.

SUBMITTER: Jin H 

PROVIDER: S-EPMC3041642 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature