Neuronal apoptosis is a highly conserved cellular mechanism playing an integral role in the development of the nervous system. Neuronal precursors proceed through the cell cycle during development to produce a far larger number of neurons than will be eventually needed. As much as half of these originally produced cells are later eliminated by apoptosis during a restricted embryonic period (1,2). Surviving neurons are thought to be ones that receive correct trophic input from their targets; therefore it is believed that one of the main functions of this developmental cell death is to adjust the number of innervating neurons to the size of their target cell population.
While neuronal apoptosis plays an essential role in the development of the nervous system, it is also an underlying element in neurodegenerative diseases. The intracellular mechanisms regulating neuronal cell death are beginning to be understood. Several observations raise the possibility that the mechanisms for control of cell division and cell death are related. Most apparent is the observation that dividing cells and dying cells share gross morphological and structural features. For cell division to occur, chromosomes must be replicated, condensed, segregated, and decondensed. The mitotic spindle must be assembled and disassembled, and the nuclear membrane must be broken down and rebuilt (3). During apoptotic cell death, chromatin becomes condensed, marginated, and fragmented (4). Dividing cells round-up, become less adherent, and their membranes invaginate as cytokinesis begins (3). With apoptotic cells the membrane rounds-up, becomes less adherent, and blebs, eventually pinching off membrane-enclosed nuclear and cytosolic remnants called apoptotic bodies (4). Thus, it appears the transient and reversible structural changes involving chromatin condensation, cell rounding, and cytoskeletal rearrangements that facilitate cell division, occur irreversibly and with destructive consequences during cell death.
Supporting these morphological observations, a growing body of evidence over the last decade has indicated that, remarkably, the underlying molecular mechanism of cell death in the central nervous system (CNS) is also intimately linked to the process of cell division. In a variety of neurodegenerative conditions in humans and rodents, mitotic markers have been observed in neurons at risk for death. Beyond correlation, studies have shown that experimentally driving the cell cycle in a mature neuron leads to cell death rather than cell division (5-9) and blocking cell cycle initiation can prevent or delay many types of neuronal cell death (10-16). These observations, correlations, and studies have lead
Oxidative Stress and Neurodegenerative Disorders Edited by G. Ali Qureshi and S. Hassan Parvez
© 2007 Elsevier B.V. All rights reserved.
to the hypothesis that deregulation of the cell cycle can either directly trigger apoptosis or increase sensitivity to apoptotic inducers. Among the stimuli implicated in promoting cell cycle function or co-opting the components of the cell cycle machinery to promote apoptosis is oxidative stress.
Reactive oxygen species (ROS) production inherent to oxidative stress is generally associated with neuronal apoptosis. In fact, oxidative stress has been implicated to play a role in acute and chronic degenerative disorders such as ischemic stroke, Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and ataxia telangiectasia (AT) (17-25). The discovery that oxidative stress can trigger a program of cell death in neurons with features of apoptosis (26) was significant as it suggested that oxidative stress does not always lead to random and disordered cell damage. It also raised the possibility that free radicals might actually be messengers used by cells to trigger an endogenous program of cell suicide. Indeed, as oxidative stress is often a marker of cells in which a failure of homeostasis has taken place, the notion that oxidants can be a signal for activating the cell death pathway holds great appeal. Consequently, coherent schemes by which free radicals acting as second messengers might trigger and execute cell death pathways have emerged. In this chapter, evidence that supports the growing convergence between the cell cycle's involvement in neuronal cell death and the ability of oxidants to promote cell cycle functions is examined and summarized.
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