Mechanisms underlying neuronal death induced by chromogranin A-activated microglia.
The neurotoxic effects of activated microglia in neurodegenerative diseases are well established. We recently provided evidence that chromogranin A (CGA), a multifunctional protein localized in dystrophic neurites and in senile plaques, induces an activated phenotype and secretion of neurotoxins by rat microglia in culture. In the present study, we focused on the mechanisms underlying neuronal degeneration triggered by CGA-activated microglia. We found that neuronal death exhibits apoptotic features, characterized by the externalization of phosphatidylserine and the fragmentation of DNA. Microglial neurotoxins markedly stimulate the phosphorylation and activity of neuronal p38 mitogen-activated protein kinase and provoke the release of mitochondrial cytochrome c, which precedes apoptosis. Inhibition of p38 kinase with SB 203580 partially protects neurons from death induced by CGA-activated microglia. Furthermore, neurons are also protected by Fas-Fc, which antagonizes the interactions between the death receptor Fas and its ligand FasL and by cell-permeable peptides that inhibit caspases 8 and 3. Thus, CGA triggers the release of microglial neurotoxins that mobilize several death-signaling pathways in neurons. Our results further support the idea that CGA, which is up-regulated in many neuropathologies, represents a potent endogeneous inflammatory factor possibly responsible for neuronal degeneration.
Ciesielski-Treska
J
J
Unité INSERM U-338 de Biologie de la Communication Cellulaire, Centre de Neurochimie, 5 rue Blaise Pascal, 67084 Strasbourg Cedex, France. ciesielski-tresa@neurochem.u-strasbg.fr
Ulrich
G
G
Chasserot-Golaz
S
S
Zwiller
J
J
Revel
M O
MO
Aunis
D
D
Bader
M F
MF
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002417:Cattle; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002837:Chromaffin Granules / Q000737:chemistry; D053379:Chromogranin A; D002864:Chromogranins / Q000302:isolation & purification / Q000494:pharmacology*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D003574:Cytochrome c Group / Q000032:analysis; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins; D010718:Phosphatidylserines / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D019014:fas Receptor / Q000276:immunology / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D053379:Chromogranin A; D002864:Chromogranins; D017077:Culture Media, Conditioned; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D007093:Imidazoles; D008562:Membrane Glycoproteins; D009498:Neurotoxins; D010718:Phosphatidylserines; D011725:Pyridines; C506153:chromogranin A, rat; D019014:fas Receptor; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580