| First Author | Jin H | Year | 2011 |
| Journal | J Neurosci | Volume | 31 |
| Issue | 6 | Pages | 2035-51 |
| PubMed ID | 21307242 | Mgi Jnum | J:180940 |
| Mgi Id | MGI:5308188 | Doi | 10.1523/JNEUROSCI.5634-10.2011 |
| Citation | Jin H, et al. (2011) alpha-Synuclein negatively regulates protein kinase Cdelta expression to suppress apoptosis in dopaminergic neurons by reducing p300 histone acetyltransferase activity. J Neurosci 31(6):2035-51 |
| abstractText | We recently demonstrated that protein kinase Cdelta (PKCdelta), 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 (alphasyn), a protein associated with the pathogenesis of Parkinson's disease, and PKCdelta, in which alphasyn negatively modulates the p300- and nuclear factor-kappaB (NFkappaB)-dependent transactivation to downregulate proapoptotic kinase PKCdelta expression and thereby protects against apoptosis in dopaminergic neuronal cells. Stable expression of human wild-type alphasyn at physiological levels in dopaminergic neuronal cells resulted in an isoform-dependent transcriptional suppression of PKCdelta expression without changes in the stability of mRNA and protein or DNA methylation. The reduction in PKCdelta transcription was mediated, in part, through the suppression of constitutive NFkappaB activity targeted at two proximal PKCdelta promoter kappaB sites. This occurred independently of NFkappaB/IkappaBalpha (inhibitor of kappaBalpha) nuclear translocation but was associated with decreased NFkappaB-p65 acetylation. Also, alphasyn reduced p300 levels and its HAT (histone acetyltransferase) activity, thereby contributing to diminished PKCdelta transactivation. Importantly, reduced PKCdelta and p300 expression also were observed within nigral dopaminergic neurons in alphasyn-transgenic mice. These findings expand the role of alphasyn in neuroprotection by modulating the expression of the key proapoptotic kinase PKCdelta in dopaminergic neurons. |
