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Poly(ADP-ribose) polymerase-1 protects neurons against apoptosis induced by oxidative stress.
Cell Death Differ. 2007 Jun; 14(6):1211-21.CD

Abstract

In neurons, DNA is prone to free radical damage, although repair mechanisms preserve the genomic integrity. However, activation of the DNA repair system, poly(ADP-ribose) polymerase (PARP-1), is thought to cause neuronal death through NAD+ depletion and mitochondrial membrane potential (delta psi(m)) depolarization. Here, we show that abolishing PARP-1 activity in primary cortical neurons can either enhance or prevent apoptotic death, depending on the intensity of an oxidative stress. Only in severe oxidative stress does PARP-1 activation result in NAD+ and ATP depletion and neuronal death. To investigate the role of PARP-1 in an endogenous model of oxidative stress, we used an RNA interference (RNAi) strategy to specifically knock down glutamate-cysteine ligase (GCL), the rate-limiting enzyme of glutathione biosynthesis. GCL RNAi spontaneously elicited a mild type of oxidative stress that was enough to stimulate PARP-1 in a Ca2+-calmodulin kinase II-dependent manner. GCL RNAi-mediated PARP-1 activation facilitated DNA repair, although neurons underwent delta psi(m) loss followed by some apoptotic death. PARP-1 inhibition did not prevent delta psi(m) loss, but enhanced the vulnerability of neurons to apoptosis upon GCL silencing. Conversely, mild expression of PARP-1 partially prevented to GCL RNAi-dependent apoptosis. Thus, in the mild progressive damage likely occur in neurodegenerative diseases, PARP-1 activation plays a neuroprotective role that should be taken into account when considering therapeutic strategies.

Authors+Show Affiliations

Unidad de Investigación, Hospital Universitario de Salamanca-Instituto de Estudios Ciencias de la Salud de Castilla y León, Salamanca, Spain.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17347665

Citation

Diaz-Hernandez, J I., et al. "Poly(ADP-ribose) Polymerase-1 Protects Neurons Against Apoptosis Induced By Oxidative Stress." Cell Death and Differentiation, vol. 14, no. 6, 2007, pp. 1211-21.
Diaz-Hernandez JI, Moncada S, Bolaños JP, et al. Poly(ADP-ribose) polymerase-1 protects neurons against apoptosis induced by oxidative stress. Cell Death Differ. 2007;14(6):1211-21.
Diaz-Hernandez, J. I., Moncada, S., Bolaños, J. P., & Almeida, A. (2007). Poly(ADP-ribose) polymerase-1 protects neurons against apoptosis induced by oxidative stress. Cell Death and Differentiation, 14(6), 1211-21.
Diaz-Hernandez JI, et al. Poly(ADP-ribose) Polymerase-1 Protects Neurons Against Apoptosis Induced By Oxidative Stress. Cell Death Differ. 2007;14(6):1211-21. PubMed PMID: 17347665.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Poly(ADP-ribose) polymerase-1 protects neurons against apoptosis induced by oxidative stress. AU - Diaz-Hernandez,J I, AU - Moncada,S, AU - Bolaños,J P, AU - Almeida,A, Y1 - 2007/03/09/ PY - 2007/3/10/pubmed PY - 2007/12/6/medline PY - 2007/3/10/entrez SP - 1211 EP - 21 JF - Cell death and differentiation JO - Cell Death Differ VL - 14 IS - 6 N2 - In neurons, DNA is prone to free radical damage, although repair mechanisms preserve the genomic integrity. However, activation of the DNA repair system, poly(ADP-ribose) polymerase (PARP-1), is thought to cause neuronal death through NAD+ depletion and mitochondrial membrane potential (delta psi(m)) depolarization. Here, we show that abolishing PARP-1 activity in primary cortical neurons can either enhance or prevent apoptotic death, depending on the intensity of an oxidative stress. Only in severe oxidative stress does PARP-1 activation result in NAD+ and ATP depletion and neuronal death. To investigate the role of PARP-1 in an endogenous model of oxidative stress, we used an RNA interference (RNAi) strategy to specifically knock down glutamate-cysteine ligase (GCL), the rate-limiting enzyme of glutathione biosynthesis. GCL RNAi spontaneously elicited a mild type of oxidative stress that was enough to stimulate PARP-1 in a Ca2+-calmodulin kinase II-dependent manner. GCL RNAi-mediated PARP-1 activation facilitated DNA repair, although neurons underwent delta psi(m) loss followed by some apoptotic death. PARP-1 inhibition did not prevent delta psi(m) loss, but enhanced the vulnerability of neurons to apoptosis upon GCL silencing. Conversely, mild expression of PARP-1 partially prevented to GCL RNAi-dependent apoptosis. Thus, in the mild progressive damage likely occur in neurodegenerative diseases, PARP-1 activation plays a neuroprotective role that should be taken into account when considering therapeutic strategies. SN - 1350-9047 UR - https://www.unboundmedicine.com/medline/citation/17347665/Poly_ADP_ribose__polymerase_1_protects_neurons_against_apoptosis_induced_by_oxidative_stress_ L2 - https://doi.org/10.1038/sj.cdd.4402117 DB - PRIME DP - Unbound Medicine ER -