Journal
NEUROSCIENCE
Volume 145, Issue 4, Pages 1267-1272Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2006.09.034
Keywords
DNA; transcription; inflammation; cell death; oxidative stress
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Funding
- NINDS NIH HHS [NS14543] Funding Source: Medline
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Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that contributes to both neuronal death and survival under stress conditions. PARP-1 is the most abundant of several PARP family members, accounting for more than 85% of nuclear PARP activity, and is present in all nucleated cells of multicellular animals. When activated by DNA damage, PARP-1 consumes nicotinamide adenine dinucleotide (NAD(+)) to form branched polymers of ADP-ribose on target proteins. This process can have at least three important consequences in the CNS, depending on the cell type and the extent of DNA damage: 1) Poly(ADP-ribose) formation on histones and on enzymes involved in DNA repair can prevent sister chromatid exchange and facilitate base-excision repair; 2) poly(ADP-ribose) formation can influence the action of transcription factors, notably nuclear factor KB, and thereby promote inflammation; and 3) extensive PARP-1 activation can promote neuronal death through mechanisms involving NAD(+) depletion and release of apoptosis inducing factor from the mitochondria. PARP-1 activation is thereby a key mediator of neuronal death during excitotoxicity, ischemia, and oxidative stress, and PARP-1 gene deletion or pharmacological inhibition can markedly improve neuronal survival in these settings. PARP-1 activation has also been identified in Alzheimer's disease and in experimental allergic encephalitis, but the role of PARP-1 in these disorders remains to be established. (C) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.
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