Pathological prion protein exposure switches on neuronal mitogen-activated protein kinase pathway resulting in microglia recruitment.
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.
Marella
Mathieu
M
Institut de Pharmacologie Moléculaire et Cellulaire, Unité Mixte de Recherche 6097, Centre National de la Recherche Scientifique 660, route des lucioles, 06560 Valbonne, France.
Gaggioli
Cédric
C
Batoz
Michèle
M
Deckert
Marcel
M
Tartare-Deckert
Sophie
S
Chabry
Joëlle
J
D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D051766:Early Growth Response Protein 1; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D017874:Immediate-Early Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D018621:PrPC Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D050807:ets-Domain Protein Elk-1
D018946:Chemokine CCL5; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D005419:Flavonoids; D017874:Immediate-Early Proteins; C099945:Nab2 protein, mouse; D009363:Neoplasm Proteins; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one