title: Role of proteolytic activation of protein kinase Cδ in the pathogenesis of prion disease.
abstract: Prion diseases are infectious and inevitably fatal neurodegenerative diseases characterized by prion replication, widespread protein aggregation and spongiform degeneration of major brain regions controlling motor function. Oxidative stress has been implicated in prion-related neuronal degeneration, but the molecular mechanisms underlying prion-induced oxidative damage are not well understood. In this study, we evaluated the role of oxidative stress-sensitive, pro-apoptotic protein kinase Cδ (PKCδ) in prion-induced neuronal cell death using cerebellar organotypic slice cultures (COSC) and mouse models of prion diseases. We found a significant upregulation of PKCδ in RML scrapie-infected COSC, as evidenced by increased levels of both PKCδ protein and its mRNA. We also found an enhanced regulatory phosphorylation of PKCδ at its two regulatory sites, Thr505 in the activation loop and Tyr311 at the caspase-3 cleavage site. The prion infection also induced proteolytic activation of PKCδ in our COSC model. Immunohistochemical analysis of scrapie-infected COSC revealed loss of PKCδ positive Purkinje cells and enhanced astrocyte proliferation. Further examination of PKCδ signaling in the RML scrapie adopted in vivo mouse model showed increased proteolytic cleavage and Tyr 311 phosphorylation of the kinase. Notably, we observed a delayed onset of scrapie-induced motor symptoms in PKCδ knockout (PKCδ(-/-)) mice as compared with wild-type (PKCδ(+/+)) mice, further substantiating the role of PKCδ in prion disease. Collectively, these data suggest that PKCδ signaling likely plays a role in the neurodegenerative processes associated with prion diseases.
authors.forename: Dilshan S
authors.initials: DS
authors.lastname: Harischandra
authors.forename: Naveen
authors.initials: N
authors.lastname: Kondru
authors.forename: Dustin P
authors.initials: DP
authors.lastname: Martin
authors.forename: Arthi
authors.initials: A
authors.lastname: Kanthasamy
authors.forename: Huajun
authors.initials: H
authors.lastname: Jin
authors.forename: Vellareddy
authors.initials: V
authors.lastname: Anantharam
authors.forename: Anumantha G
authors.initials: AG
authors.lastname: Kanthasamy
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D017096:Prion Diseases / Q000201:enzymology*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D059748:Proteolysis
chemical_list: D051745:Protein Kinase C-delta