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Direct Quantitation of Poly(ADP‐Ribose) Polymerase (PARP) Activity as a Means to Distinguish Necrotic and Apoptotic Death in Cell and Tissue Samples

The ability to regulate cell death is essential to the life of a multicellular organism, and two extremes on the cell-death spectrum are apoptosis and necrosis. Apoptosis is an energydependent cell-death program that enables the elimination of unwanted cells at distinct times and through defined mechanisms. Because apoptosis occurs without spillage of cellular contents into the extracellular environment, this death does not lead to inflammation. In contrast, necrosis arises from blunt traumatic injury, oxygen depravation, or other gross cellular insult, and the rupture of the cellular membrane during necrotic death provokes an inflammatory response. Both forms of cell death are observed in diseased tissue. For instance, much of the neurodegeneration observed in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS) probably arises from premature apoptosis, while damage seen in hemorrhagic shock and stroke patients can be due to massive necrotic death. Although apoptosis and necrosis represent two fundamentally different forms of death, they can be quite difficult to distinguish experimentally. Typically, several hallmarks must be observed before it can be conclusively stated that apoptotic death has occurred. These involve time-, labor-, and cost-intensive procedures such as immunoblotting, flow cytometry, and microscopy. The enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is differentially processed in apoptosis and necrosis, and therefore its activity can potentially be used as a means of distinguishing these two forms of cell death (Scheme 1A). In response to mild DNA damage, PARP-1 catalyzes the formation of ADP-ribose polymers (from NAD) onto protein acceptors; this response is part of the machinery that allows the DNA to be repaired and the cell to be saved. In contrast, during more severe DNA damage, the cell activates the apoptotic cascade, and PARP-1 is cleaved by caspases into 89 and 24 kDa sub-