Contributions of poly(ADP-ribose) polymerase-1 and -2 to nuclear translocation of apoptosis-inducing factor and injury from focal cerebral ischemia.

Abstract

Excessive oxidative damage to DNA leads to activation of poly(ADP-ribose) polymerase-1 (PARP-1), accumulation of PAR polymers, translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus, and cell death. In this study, we compared the effect of gene deletion of PARP-1 and PARP-2, enzymes activated by DNA oxidative damage, in male mice subjected to 2 h of focal cerebral ischemia. Infarct volume at 3 days of reperfusion was markedly decreased to a similar extent in PARP-1- and PARP-2-null mice. The ischemia-induced increase in nuclear AIF accumulation was largely suppressed in both knockout genotypes. The transient increase in PAR during early reperfusion was nearly blocked in PARP-1-null mice, but only moderately decreased at 1-h reperfusion in PARP-2-null mice. Differences in the tissue volume at risk, as assessed by arterial casts and autoradiographic analysis of regional blood flow, did not fully account for the large reductions in AIF translocation and infarct volume in both PARP null mice. Cell death was attenuated in PARP-2-null neurons exposed to a submaximal concentration of 100 microM NMDA for 5 min, but not in those exposed to a near-maximal toxic concentration of 500 microM NMDA. We conclude that PARP-2 contributes substantially to nuclear translocation of AIF and infarct size after transient focal cerebral ischemia in male mice, but that protection is disproportionate to the attenuation of overall PARP activity.

• Authors: Xiaoling Li, Judith A Klaus, Jian Zhang, Zhenfeng Xu, Kathleen K Kibler, Shaida A Andrabi, Karthik Rao, Zeng-Jin Yang, Ted M Dawson, Valina L Dawson, Raymond C Koehler
• Journal: Journal of neurochemistry (J Neurochem) Vol. 113 Issue 4 Pg. 1012-22 (May 2010) ISSN: 1471-4159 [Electronic] England
• PMID: 20236222 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Inducing Factor
• Excitatory Amino Acid Agonists
• Pdcd8 protein, mouse
• Glutamic Acid
• Parp1 protein, mouse
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• Parp2 protein, mouse

Topics

• Active Transport, Cell Nucleus (physiology)
• Animals
• Apoptosis Inducing Factor (genetics, metabolism)
• Brain (metabolism, physiopathology)
• Brain Ischemia (genetics, metabolism, physiopathology)
• Cell Nucleus (metabolism)
• Cells, Cultured
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Agonists (toxicity)
• Glutamic Acid (metabolism, toxicity)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nerve Degeneration (genetics, metabolism, physiopathology)
• Neurons (metabolism)
• Oxidative Stress (drug effects, physiology)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Reperfusion Injury (genetics, metabolism, physiopathology)