Intrinsic Mechanisms of Poly(ADP-Ribose) Neurotoxicity: Three Hypotheses

Poly(ADP-ribose) (PAR) is a branched and negatively charged polymeric macromolecule formed by poly(ADP-ribose) polymerases. Targeting of PAR onto acceptor proteins affects their functioning and regulates cellular homeostasis. A large body of evidence demonstrates that increased neo-formation of PAR has a crucial role in neurodegeneration. Consistently, strategies aimed at reducing PAR synthesis are of therapeutic relevance to treatment of several experimental neurodegenerative diseases. However, how PAR causes neuronal death is still elusive. This review provides an appraisal of the possible molecular mechanisms underlying PAR neurotoxicity, highlighting the pleiotypic effects of the polymer on neural cells exposed to different stressful conditions.