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ARTICLE, Cellular/Molecular

Homocysteine Elicits a DNA Damage Response in Neurons That Promotes Apoptosis and Hypersensitivity to Excitotoxicity

Inna I. Kruman, Carsten Culmsee, Sic L. Chan, Yuri Kruman, Zhihong Guo, LaRoy Penix and Mark P. Mattson
Journal of Neuroscience 15 September 2000, 20 (18) 6920-6926; DOI: https://doi.org/10.1523/JNEUROSCI.20-18-06920.2000
Inna I. Kruman
1Laboratory of Neurosciences, National Institute on Aging, Baltimore, Maryland 21224, and
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Carsten Culmsee
2Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536
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Sic L. Chan
1Laboratory of Neurosciences, National Institute on Aging, Baltimore, Maryland 21224, and
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Yuri Kruman
1Laboratory of Neurosciences, National Institute on Aging, Baltimore, Maryland 21224, and
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Zhihong Guo
1Laboratory of Neurosciences, National Institute on Aging, Baltimore, Maryland 21224, and
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LaRoy Penix
2Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536
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Mark P. Mattson
1Laboratory of Neurosciences, National Institute on Aging, Baltimore, Maryland 21224, and
2Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536
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Abstract

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.

  • calcium
  • caspase
  • mitochondrial transmembrane potential
  • NAD
  • PARP
  • stroke
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The Journal of Neuroscience: 20 (18)
Journal of Neuroscience
Vol. 20, Issue 18
15 Sep 2000
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Homocysteine Elicits a DNA Damage Response in Neurons That Promotes Apoptosis and Hypersensitivity to Excitotoxicity
Inna I. Kruman, Carsten Culmsee, Sic L. Chan, Yuri Kruman, Zhihong Guo, LaRoy Penix, Mark P. Mattson
Journal of Neuroscience 15 September 2000, 20 (18) 6920-6926; DOI: 10.1523/JNEUROSCI.20-18-06920.2000

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Homocysteine Elicits a DNA Damage Response in Neurons That Promotes Apoptosis and Hypersensitivity to Excitotoxicity
Inna I. Kruman, Carsten Culmsee, Sic L. Chan, Yuri Kruman, Zhihong Guo, LaRoy Penix, Mark P. Mattson
Journal of Neuroscience 15 September 2000, 20 (18) 6920-6926; DOI: 10.1523/JNEUROSCI.20-18-06920.2000
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Keywords

  • calcium
  • caspase
  • mitochondrial transmembrane potential
  • NAD
  • PARP
  • stroke

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