Chromogranin A induces a neurotoxic phenotype in brain microglial cells.
Chromogranin A (CGA) belongs to a multifunctional protein family widely distributed in secretory vesicles in neurons and neuroendocrine cells. Within the brain, CGA is localized in neurodegenerative areas associated with reactive microglia. By using cultured rodent microglia, we recently described that CGA induces an activated phenotype and the generation of nitric oxide. These findings led us to examine whether CGA might affect neuronal survival, expression of neurofilaments, and high affinity gamma-aminobutyric acid uptake in neurons cultured in the presence or absence of microglial cells. We found that CGA was unable to exert a direct toxic effect on neurons but provoked neuronal injury and degeneration in the presence of microglial cells. These effects were observed with natural and recombinant CGA and with a recombinant N-terminal fragment corresponding to residues 1-78. CGA stimulated microglial cells to secrete heat-stable diffusible neurotoxic agents. CGA also induced a marked accumulation of nitric oxide and tumor necrosis factor-alpha by microglia, but we could not establish a direct correlation between the levels of nitric oxide and tumor necrosis factor-alpha and the neuronal damage. The possibility that CGA represents an endogenous factor that triggers the microglial responses responsible for the pathogenesis of neuronal degeneration is discussed.
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.
Ulrich
G
G
Taupenot
L
L
Chasserot-Golaz
S
S
Corti
A
A
Aunis
D
D
Bader
M F
MF
D000818:Animals; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053379:Chromogranin A; D002864:Chromogranins / Q000633:toxicity*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D017628:Microglia / Q000187:drug effects*; D019636:Neurodegenerative Diseases / Q000209:etiology; D009474:Neurons / Q000166:cytology; D009569:Nitric Oxide / Q000378:metabolism; D009952:Ornithine / Q000031:analogs & derivatives / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000493:pharmacokinetics
C506150:CHGA protein, human; D053379:Chromogranin A; D002864:Chromogranins; D017077:Culture Media, Conditioned; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C065027:N(G)-iminoethylornithine; D005680:gamma-Aminobutyric Acid; D009952:Ornithine; D013936:Thymidine