PT  - JOURNAL ARTICLE
AU  - Kruman, Inna I.
AU  - Culmsee, Carsten
AU  - Chan, Sic L.
AU  - Kruman, Yuri
AU  - Guo, Zhihong
AU  - Penix, LaRoy
AU  - Mattson, Mark P.
TI  - Homocysteine Elicits a DNA Damage Response in Neurons That Promotes Apoptosis and Hypersensitivity to Excitotoxicity
AID  - 10.1523/JNEUROSCI.20-18-06920.2000
DP  - 2000 Sep 15
TA  - The Journal of Neuroscience
PG  - 6920--6926
VI  - 20
IP  - 18
4099  - http://www.jneurosci.org/content/20/18/6920.short
4100  - http://www.jneurosci.org/content/20/18/6920.full
SO  - J. Neurosci.2000 Sep 15; 20
AB  - 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.