title: α-Synuclein negatively regulates protein kinase Cδ expression to suppress apoptosis in dopaminergic neurons by reducing p300 histone acetyltransferase activity.
abstract: We recently demonstrated that protein kinase Cδ (PKCδ), 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 α-synuclein (αsyn), a protein associated with the pathogenesis of Parkinson's disease, and PKCδ, in which αsyn negatively modulates the p300- and nuclear factor-κB (NFκB)-dependent transactivation to downregulate proapoptotic kinase PKCδ expression and thereby protects against apoptosis in dopaminergic neuronal cells. Stable expression of human wild-type αsyn at physiological levels in dopaminergic neuronal cells resulted in an isoform-dependent transcriptional suppression of PKCδ expression without changes in the stability of mRNA and protein or DNA methylation. The reduction in PKCδ transcription was mediated, in part, through the suppression of constitutive NFκB activity targeted at two proximal PKCδ promoter κB sites. This occurred independently of NFκB/IκBα (inhibitor of κBα) nuclear translocation but was associated with decreased NFκB-p65 acetylation. Also, αsyn reduced p300 levels and its HAT (histone acetyltransferase) activity, thereby contributing to diminished PKCδ transactivation. Importantly, reduced PKCδ and p300 expression also were observed within nigral dopaminergic neurons in αsyn-transgenic mice. These findings expand the role of αsyn in neuroprotection by modulating the expression of the key proapoptotic kinase PKCδ in dopaminergic neurons.
authors.affiliation: Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Huajun
authors.initials: H
authors.lastname: Jin
authors.forename: Arthi
authors.initials: A
authors.lastname: Kanthasamy
authors.forename: Anamitra
authors.initials: A
authors.lastname: Ghosh
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Yang
authors.forename: Vellareddy
authors.initials: V
authors.lastname: Anantharam
authors.forename: Anumantha G
authors.initials: AG
authors.lastname: Kanthasamy
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation / Q000379:methods; D019295:Computational Biology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D013378:Substantia Nigra / Q000166:cytology; D014162:Transfection / Q000379:methods; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D053148:Caspase 3; D004298:Dopamine; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D007770:L-Lactate Dehydrogenase; D051745:Protein Kinase C-delta; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014446:Tyrosine 3-Monooxygenase; D051844:alpha-Synuclein; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor