Neither energy collapse nor transcription underlie in vitro neurotoxicity of poly(ADP-ribose) polymerase hyper-activation

• Published in: Neurochemistry international 2007, Vol.50 (1), p.203-210
• Main Authors: Fossati, Silvia, Cipriani, Giulia, Moroni, Flavio, Chiarugi, Alberto
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; AIF; Animals; Biological and medical sciences; Caspases - metabolism; Cell Death; Energy failure; Enzyme Activation; Fundamental and applied biological sciences. Psychology; In Vitro Techniques; MAP Kinase Kinase 4 - metabolism; Methylnitronitrosoguanidine - pharmacology; Mice; NAD - metabolism; Neuronal apoptosis; PARP; Poly(ADP-ribose) Polymerases - metabolism; Transcription; Transcription, Genetic; Vertebrates: nervous system and sense organs
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2006.08.009

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-1-dependent apoptotic neuronal death, and support the existence of a poly(ADP-ribose)-mediated death signaling targeting mitochondria.