Poly(ADP-ribose) polymerase-1 protects neurons against apoptosis induced by oxidative stress (original) (raw)
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Seminars in cell & developmental biology, 2017
Neurodegeneration is a salient feature of chronic refractory brain disorders like Alzheimer's, Parkinson's, Huntington's, amyotropic lateral sclerosis and acute conditions like cerebral ischemia/reperfusion etc. The pathological protein aggregates, mitochondrial mutations or ischemic insults typifying these disease conditions collude with and intensify existing oxidative stress and attendant mitochondrial dysfunction. Interlocking these mechanisms is poly(ADP-ribose) polymerase (PARP-1) hyperactivation that invokes a distinct form of neuronal cell death viz., 'parthanatos'. PARP-1, a typical 'moonlighting protein' by virtue of its ability to poly(ADP-ribosyl)ate a plethora of cellular proteins exerts diverse functions that impinge significantly on cellular processes. In addition, its interactions with various nuclear proteins like transcription factors and chromatin modifiers elicit varied transcriptional outcomes that wield pathological cellular response...
British Journal of Pharmacology, 2009
Background and purpose: Poly(ADP-ribose) polymerases (PARP)-1 and PARP-2 play complementary tasks in the maintenance of genomic integrity, but their role in cell death or survival processes is rather different. A recently described series of selective PARP-2 inhibitors (UPF-1035, UPF-1069) were used to study the role of PARP-1 and PARP-2 in post-ischaemic brain damage. Experimental approach: We evaluated post-ischaemic brain damage in two different in vitro models: rat organotypic hippocampal slices exposed to oxygen-glucose deprivation (OGD) for 20-30 min, a model characterized by apoptosis-like cell death and mouse mixed cortical cell cultures exposed to 60 min OGD, a model in which cells die with mostly necrosis-like features. Key results: In organotypic hippocampal slices, PARP-2 inhibition with UPF-1069 (0.01-1 mmol•L-1) caused a concentrationdependent exacerbation (up to 155%) of OGD-induced CA1 pyramidal cell death. Higher concentrations, acting on both PARP-1 and PARP-2, had no effect on OGD injury. In mouse mixed cortical cells exposed to OGD, on the contrary, UPF-1069 (1-10 mmol•L-1) significantly reduced post-ischaemic damage. Conclusion and implications: Selective PARP-2 inhibitors increased post-OGD cell death in a model characterized by loss of neurons through a caspase-dependent, apoptosis-like process (hippocampal slice cultures), but they reduced post-OGD damage and increased cell survival in a model characterized by a necrosis-like process (cortical neurons). UPF-1069 may be a valuable tool to explore the function of PARP-2 in biological systems and to examine the different roles of PARP isoenzymes in the mechanisms of cell death and survival.
Poly(ADP-ribose)polymerase 1 (PARP-1) and postischemic brain damage
Current Opinion in Pharmacology, 2008
Poly(ADP-ribose)polymerases (PARPs) are enzymes that are able to catalyze the transfer of ADP-ribose units from NAD to substrate proteins and are particularly abundant in cell nuclei where they play key roles in the maintenance of genomic integrity, control of cell cycle and gene expression. Brain ischemia overactivates PARPs and PARP-deficient mice or animal treated with PARP inhibitors have a drastically reduced brain damage in various stroke models. PARP 'overactivation' occurs not only in neurons but also in astrocytes, microglial cells, endothelia, and infiltrating leukocytes. The ensuing cell death occurs through various molecular mechanisms: a) excessive ATP use for NAD synthesis and inhibition of mitochondrial function with subsequent energy failure (particularly important in neurons); b) apoptosis-inducing factor (AIF) translocation from the mitochondria to the nucleus (present in neurons, endothelial, and other cells); c) excessive expression of inflammatory mediators (well demonstrated in glial cells) or d) reduced expression of prosurvival factors. Thus PARPs seem to play key roles in postischemic brain damage and are now considered interesting targets for therapies aimed at reducing stroke pathology.
PARP-1 Modulates Amyloid Beta Peptide-Induced Neuronal Damage
PLoS ONE, 2013
Amyloid beta peptide (Ab) causes neurodegeneration by several mechanisms including oxidative stress, which is known to induce DNA damage with the consequent activation of poly (ADP-ribose) polymerase (PARP-1). To elucidate the role of PARP-1 in the neurodegenerative process, SH-SY5Y neuroblastoma cells were treated with Ab 25-35 fragment in the presence or absence of MC2050, a new PARP-1 inhibitor. Ab 25-35 induces an enhancement of PARP activity which is prevented by cell pre-treatment with MC2050. These data were confirmed by measuring PARP-1 activity in CHO cells transfected with amylod precursor protein and in vivo in brains specimens of TgCRND8 transgenic mice overproducing the amyloid peptide. Following Ab 25-35 exposure a significant increase in intracellular ROS was observed. These data were supported by the finding that Ab 25-35 induces DNA damage which in turn activates PARP-1. Challenge with Ab 25-35 is also able to activate NF-kB via PARP-1, as demonstrated by NF-kB impairment upon MC2050 treatment. Moreover, Ab 25-35 via PARP-1 induces a significant increase in the p53 protein level and a parallel decrease in the anti-apoptotic Bcl-2 protein. These overall data support the hypothesis of PARP-1 involvment in cellular responses induced by Ab and hence a possible rationale for the implication of PARP-1 in neurodegeneration is discussed.
Neurochemistry International, 2007
Poly(ADP-ribose)polymerase-1 (PARP-1) overactivation is a key event in neurodegeneration but the underlying molecular mechanisms wait to be unequivocally identified. Energy failure, transcriptional derangement and deadly nucleus-mitochondria cross-talk have been proposed as mechanisms responsible for PARP-1 neurotoxicity. In this study, we sought to determine how these mechanisms contributes to PARP-1-dependent neuronal death. We report that the PARP-1 activating agent methyl-nitrosoguanidine (MNNG) caused poly(ADP-ribosyl)ation-dependent death of pure mouse cortical neurons in culture. Upon PARP-1 hyperactivation, NAD and ATP storages only partially decreased, neurons rapidly acquired apoptotic morphology, apoptosis inducing factor and cytochrome c were released from mitochondria and caspase activation occurred. No evidence for p53 activation was found, lactate dehydrogenase release occurred only 18 h later, and JNK kinase was constitutively activated and not affected by PARP-1 activation. The PARP-1 inhibitors 6-(5)H-phenanthridinone and N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide (PJ-34) prevented nucleotide depletion and cell death, whereas the transcription inhibitor actinomycin D did not affect PARP-1-dependent neurotoxicity. Together, our findings provide the first evidence that neither energy collapse nor transcriptional changes are involved in PARP-1dependent apoptotic neuronal death, and support the existence of a poly(ADP-ribose)-mediated death signaling targeting mitochondria. #
Proceedings of the National Academy of Sciences
Hyperoxia induces extensive DNA damage and lung cell death by apoptotic and nonapoptotic pathways. We analyzed the regulation of Poly(ADP-ribose)polymerase-1 (PARP-1), a nuclear enzyme activated by DNA damage, and its relation to cell death during hyperoxia in vitro and in vivo. In lung epithelial-derived A549 cells, which are known to die by necrosis when exposed to oxygen, a minimal amount of PARP-1 was cleaved, correlating with the absence of active caspase-3. Conversely, in primary lung fibroblasts, which die mainly by apoptosis, the complete cleavage of PARP-1 was concomitant to the induction of active caspase-3, as assessed by Western blot and caspase activity. Blockade of caspase activity by Z-VAD reduced the amount of cleaved PARP-1 in fibroblasts. Hyperoxia induced PARP activity in both cell types, as revealed by poly-ADPribose accumulation. In A549 cells, the final outcome of necrosis was dependent on PARP activity because it was prevented by the PARP inhibitor 3-aminobenzamide. In contrast, apoptosis of lung fibroblasts was not sensitive to 3-aminobenzamide and was not affected by PARP-1 deletion. In vivo, despite evidence of PARP activation in hyperoxia-exposed mouse lungs, absence of PARP-1 did not change the extent of lung damage, arguing for redundant oxidative stress-induced cell death pathways.
The role of PARP activation in glutamate-induced necroptosis in HT22 cells
Brain Research, 2010
Oxidative cell death contributes to neuronal cell death in many neurological diseases such as stroke, brain trauma, and Alzheimer's disease. In this study, we explored the involvement of poly(ADP-ribose)-polymerase (PARP) in oxidative stress-induced necroptosis. We showed that PJ34, a potent and specific inhibitor of PARP, can completely inhibit glutamate-induced necroptosis in HT-22 cells. This protective effect was still observed 8 h after glutamate exposure followed by PJ34 treatment. These results suggest that PARP activation plays a critical role in glutamate-induced necroptosis. We also examined the interaction between PARP and a necroptosis inhibitor called necrostatin-1 (Nec-1).
Annals of the New York Academy of Sciences, 1999
Poly(ADP-ribose) polymerase (PARP) is a DNA binding protein that uses nicotinamide adenine dinucleotide (NAD +) as a substrate. Evidence from in vitro studies on nonneuronal cells in culture have shown that when fully activated by free radical-induced DNA damage, PARP depletes cellular NAD + and consequently adenosine triphosphate (ATP) levels within a matter of minutes, and that this depletion is associated with a cell death that can be prevented by PARP inhibitors. The present in vivo study utilized the 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse, a model of central nigrostriatal dopamine neurotoxicity that recapitulates certain features of Parkinson's disease (PD), and one in which we have previously shown PARP inhibitors to be protective, 6 to examine whether MPTP acutely caused regionand time-dependent changes in levels of NAD + and ATP in the brain in vivo and whether such effects were modified by treatments with neuroprotective doses of the PARP inhibitor benzamide. The results confirm that MPTP reduces striatal ATP levels, as previously reported by Chan et al., 4 show that MPTP causes a regionally-selective (striatal and midbrain) loss of NAD + , and indicate that the PARP inhibitor benzamide can prevent these losses without interfering with MPTP-induced striatal dopamine release. These findings suggest an involvement of PARP in the control of brain energy metabolism during neurotoxic insult, provide further evidence in support of the participation of PARP in MPTP-induced neurotoxicity in vivo and suggest that PARP inhibitors might be beneficial in the treatment of PD.