NR ARRQ
AU Marella,M.; Gaggioli,C.; Batoz,M.; Deckert,M.; Tartare-Deckert,S.; Chabry,J.
TI Pathological prion protein exposure switches on neuronal mitogen-activated protein kinase pathway resulting in microglia recruitment
QU The Journal of Biological Chemistry 2005 Jan 14; 280(2): 1529-34
PT journal article
AB Transmissible spongiform encephalopathies are accompanied by the recruitment of microglial cells in the vicinity of amyloid aggregates of the pathological prion protein (PrPres). We previously showed that PrPres itself triggered the recruitment of microglia by interacting with neurons leading to the up-regulation of the expression level of chemokines, mainly RANTES (regulated on activation normal T cell expressed and secreted). The intracellular mechanisms underlying the PrPres-inducible expression of chemokines in this setting are not clear. Here we demonstrate that the mitogen-activated protein kinase pathway is switched on shortly after PrPres exposure to neurons leading to the expression of early growth response factor-1 (Egr-1), a transcription factor initially linked to differentiation and growth and to up-regulation of RANTES mRNA expression. PD98059, a selective inhibitor of extracellular signal-regulated kinase1/2 activation, resulted in a decrease of RANTES mRNA expression and as a consequence to the lowering of microglial cell migration. Neuronal overexpression of Nab2, a corepressor of Egr-1, produced similar effects. PrPres-induced chemoattraction is independent of the presence of PrPc and the laminin receptor on the neuronal cell surface. Our report is the first demonstration that PrPres exposure on neurons results in the activation of the MAP kinase signaling pathway that acts as a master switch to trigger neuronal expression of regulators of chemoattraction.
MH Animals; Cell Line; Cell Movement; Cells, Cultured; DNA-Binding Proteins/metabolism; Flavonoids/pharmacology; Gene Expression Regulation; Immediate-Early Proteins/metabolism; *MAP Kinase Signaling System/drug effects; Mice; Mice, Knockout; Microglia/*cytology; Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism; Models, Biological; Neoplasm Proteins/metabolism; Neurons/enzymology/*metabolism; Phosphorylation; PrPc Proteins/deficiency/genetics/metabolism; PrPsc Proteins/genetics/*metabolism; Proto-Oncogene Proteins/metabolism; RANTES/biosynthesis/genetics; RNA, Messenger/genetics/metabolism; Repressor Proteins/metabolism; Research Support, Non-U.S. Gov't; Transcription Factors/metabolism
AD Institut de Pharmacologie Moleculaire et Cellulaire, Unite Mixte de Recherche 6097, Centre National de la Recherche Scientifique 660, route des lucioles, 06560 Valbonne, France.
SP englisch
PO USA