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Previous Article | Next Article
The Journal of Neuroscience, September 15, 2000, 20(18):6920-6926
Homocysteine Elicits a DNA Damage Response in Neurons That Promotes Apoptosis and Hypersensitivity to Excitotoxicity
Inna I. Kruman1, Carsten Culmsee2, Sic L. Chan1, Yuri Kruman1, Zhihong Guo1, LaRoy Penix2, and Mark P. Mattson1, 2 1 Laboratory of Neurosciences, National Institute on Aging, Baltimore, Maryland 21224, and 2 Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536
Elevated plasma levels of the sulfur-containing amino acid homocysteine increase the risk for atherosclerosis, stroke, and possibly Alzheimer's disease, but the underlying mechanisms are unknown. We now report that homocysteine induces apoptosis in rat hippocampal neurons. DNA strand breaks and associated activation of poly-ADP-ribose polymerase (PARP) and NAD depletion occur rapidly after exposure to homocysteine and precede mitochondrial dysfunction, oxidative stress, and caspase activation. The PARP inhibitor 3-aminobenzamide (3AB) protects neurons against homocysteine-induced NAD depletion, loss of mitochondrial transmembrane potential, and cell death, demonstrating a requirement for PARP activation and/or NAD depletion in homocysteine-induced apoptosis. Caspase inhibition accelerates the loss of mitochondrial potential and shifts the mode of cell death to necrosis; inhibition of PARP with 3AB attenuates this effect of caspase inhibition. Homocysteine markedly increases the vulnerability of hippocampal neurons to excitotoxic and oxidative injury in cell culture and in vivo, suggesting a mechanism by which homocysteine may contribute to the pathogenesis of neurodegenerative disorders.
Key words: calcium; caspase; mitochondrial transmembrane potential; NAD; PARP; stroke
Copyright © 2000 Society for Neuroscience 0270-6474/00/20186920-07$05.00/0
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