Poly(ADP-ribosyl)ation is the post-translational modification of proteins operated by poly(ADP-ribose) polymerases (PARPs). PARPs are enzymes that are able to catalyze the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD) to target proteins and are particularly abundant in cell nuclei, where they play a key role in the maintenance of homeostasis. Poly(ADP-ribosyl)ation significantly affects protein functioning because of the high negative charge and steric hindrance conferred by the chains of poly(ADP-ribose) (PAR). PARP-1 is the founding member and the most commonly studied of these enzymes and shows the highest poly(ADP-ribosyl)ating activity. Sequences encoding novel PARPs have been identified and, overall, the PARP superfamily is a growing family of enzymes with numerous members with roles that are yet to be identified (Ame et al. 2004; Smith 2001).
Under physiological conditions, basal DNA strand breaks or cruciform DNA structures (Potaman et al. 2005) activates PARPs and ongoing cycles of PAR formation and hydrolysis onto acceptor proteins finely regulates key cellular functions such as DNA duplication, repair, and transcription (D'Amours et al. 1999; Herceg and Wang 2001; Kraus and Lis 2003) as well as mitosis (Chang et al. 2004) and protein degradation (Ullrich et al. 2001a). However, in the presence of widespread DNA damage, excessive activation of PARPs turns PAR from a homeostatic regulator into a highly cytotoxic molecule (Andrabi et al. 2006; Herceg and Wang 2001) and may cause cell death.
Neurons are particularly sensitive to deregulation of PAR homeostasis and numerous studies demonstrate that hyper-poly(ADP-ribosyl)ation is a key trigger of neurotoxicity (Ha and Snyder 2000). During the past decade, poly(ADP-ribosyl) ation has been identified as a key event in neurodegeneration occurring in a
Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy e-mail: [email protected]
large number of experimental models of brain disorders, including excitotoxicity (Mandir et al. 2000), N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism (Mandir et al. 1999), neurotrauma (Whalen et al. 1999), encephalomyelitis (Chiarugi 2002a; Scott et al. 2001), subarachnoid hemorrhage (Satoh et al. 2001), oxidative stress, amyloid neurotoxicity, neuroinflammation (Chiarugi and Moskowitz 2003; Ullrich et al. 2001b), meningitis (Koedel and Pfister 1999) and brain ischemia (Szabo and Dawson 1998).
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