CELL BIOLOGY AND METABOLISM
Chromogranin A Induces a Neurotoxic Phenotype in Brain Microglial Cells*

https://doi.org/10.1074/jbc.273.23.14339Get rights and content
Under a Creative Commons license
open access

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 γ-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-α by microglia, but we could not establish a direct correlation between the levels of nitric oxide and tumor necrosis factor-α 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.

Cited by (0)

*

This work was supported by INSERM (“Equipements Llourds”), by the Direction des Recherches, Etudes et Techniques Grant DRET 96-099, and by Université Louis Pasteur Contrat Plurifonction 94-97.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.