The role of poly(ADP-ribose) polymerase-1 in CNS disease.
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 kappaB, 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.
Kauppinen
T M
TM
Department of Neurology, University of California at San Francisco, and Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA.
Swanson
R A
RA
D000818:Animals; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002493:Central Nervous System Diseases / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D018384:Oxidative Stress / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*
C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases