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J Biol Chem, Vol. 273, Issue 23, 14339-14346, June 5, 1998
From the Unité INSERM U-338 de Biologie de la Communication
Cellulaire, Centre de Neurochimie, 5 Rue Blaise Pascal,
67084 Strasbourg Cedex, France and 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
Chromogranin A Induces a Neurotoxic Phenotype in Brain Microglial
Cells
, Department of
Biological and Technological Research, San Raffaele Scientific
Institute, 20132 Milan, Italy
-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-
by
microglia, but we could not establish a direct correlation between the
levels of nitric oxide and tumor necrosis factor- 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.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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