ABSTRACT
Cell death is a normal physiological process that plays an essential role from the beginning of embryogenesis to adulthood.1,2 Cell death is instrumental in morphogenesis, homeostasis, and differentiation. It also plays a major role in the pathogenesis of tissue damage in diseases.3-5 In the developing central nervous system, cell death plays an important role in growth and differentiation. Although mature neurons are among the most long-lived cell types in mammals, immature neurons die in large numbers during development, shaping and sculpting the developing brain.6 Neuronal cell death in developing brain is thought to be responsible for matching neuronal populations to their target areas, a process believed to be controlled by a limiting supply of target-derived growth factors7 and by afferent synaptic activity.8,9 After maturation, neurons become postmitotic and lose their ability to divide. Neuronal cell death induced by pathological or traumatic insults has a deleterious effect on the central nervous system because of the inability of the tissue to repair or replace the damaged neurons. In human brain, neuronal degeneration can occur after acute insults, such as stroke and trauma, as well as during progressive adult-onset diseases such as Parkinson’s disease and Alzheimer’s disease. Excitotoxicity plays an important role in many neuropathological conditions including stroke, Parkinson’s disease, and
Alzheimer’s disease.10,11 Effective approaches to prevent or limit neuronal cell death in these diseases remain elusive due largely to an incomplete understanding of the neuronal death pathways in vivo. Despite the fact that some biochemical features of neuronal cell death have been elucidated, the key players still remain to be identified. Recently, poly(ADP-ribose) polymerase-1 (PARP-1) has been identified as a very important mediator of neuronal cell death.12-14
Cell death was originally classified as two distinct types called apoptosis and necrosis according to their respective morphological and biochemical features (Figure 2.1).1,15-17 As more-detailed examinations of neuronal cell death are being performed, the distinctions between apoptosis and necrosis are becoming blurred. Furthermore, recent observations suggest that cell death may exist as a continuum with apoptosis and necrosis at opposite ends.18-20
Apoptosis could be executed in a programmed fashion as observed during development or be initiated under pathophysiological conditions. Apoptosis is an active cell death process characterized by chromatin condensation with extensive DNA fragmentation and nuclear pyknosis often accompanied by karyorrhexis.1,16 During apoptosis, the cytoplasm condenses and the cell shrinks while the cellular organelles
FIGURE 2.1 PARP-1 in apoptotic and necrotic cell death. Apoptotic and necrotic death are two types of cell death characterized by distinct morphological and biochemical features. Apoptotic and necrotic death are probably at opposite ends of a cell death continuum. Despite their distinct features, apoptotic and necrotic cell death may be controlled by the same subset of executor proteins. PARP-1 may be one of the cellular switches that can determine whether a cell will complete the apoptotic program or will die by necrotic cell death. In necrotic cell death, excess DNA damage leads to PARP-1 activation, massive NAD consumption, and cellular energy depletion. In apoptotic cell death, PARP-1 is cleaved by caspases and inactivated, preventing energy depletion and allowing the completion of the apoptotic program.
