PART II CELL DEATH IN TISSUES AND ORGANS

Naturally occurring neuronal cell death is common during the development of the nervous system. Depending on the neuronal population, as many as 20% to 80% of all neurons produced during embryogenesis die before the animal reaches adulthood. This regressive event functions to primarily adjust the magnitude of each neuronal population to the size or functional needs of its target field and has been recognized as a major player in establishing the definitive form of adult nervous system. Although immature neurons die physiologically in large numbers during development, mature neurons are among the most long-lived cell types in mammals. Under pathological conditions, mature neurons might activate cell death mechanisms that are known to occur in various acute and chronic neurodegenerative diseases. Pathological neuronal cell death, however, occurs through more diversified pathways than that during development. In this chapter, we review the evidence that supports the role of apoptosis during neuronal development, as well as the possible role of nonapoptotic cell death in the nervous system. We discuss the relevance of different cell death mechanisms in several neurodegenerative diseases and the potential neuroprotective targets for treatment of these diseases.

1. NATURALLY OCCURRING NEURONAL CELL DEATH

DURING DEVELOPMENT WHEN NEURONS ARE

ESTABLISHING THEIR TARGETING CONNECTIONS

1.1. Death by trophic factor deprivation

During nervous system development, the temporal phase of extensive neuronal cell death is usually confined to a well-defined period that is distinctive for each neuronal population and often coincides with the time

when the neuronal population as a whole is beginning to establish connections in its projection field. Many further experiments, which are summarized in Figure 11-1, supported the view that the target field is critical in determining the number of projecting neurons that survive. The survival of neurons during this period is highly dependent on the success of each neuron in competition for the availability of neurotrophic factors produced by their target or neighboring cells. The net result of such competition for trophic factor supply is the survival of some and death of other neurons, thereby matching the size of the target field with the number of innervating neurons. The programmed cell death of neurons also meets other adaptive needs, which include establishing optimal levels of connectivity between neuronal populations, eliminating aberrant cells or connections, regulating the size of progenitor populations, and serving transient functional needs of immature animals.

The first neurotrophic factor, nerve growth factor (NGF), was identified by Levi-Montalcini and Hamburger in 1951. Since then, the molecular mechanism of target-dependent neuronal cell death has been studied extensively in sympathetic neurons that are dependent on NGF for survival both in vivo and in vitro. In a frequently used paradigm, sympathetic neurons from superior cervical ganglion (SCG) of the embryonic day 21 rats are maintained in the presence of NGF for 5 to 7 days; the removal of NGF induces apoptotic cell death of all neurons 24 to 48 hours after NGF deprivation in culture. Inhibition of RNA and protein synthesis blocked apoptotic cell death, suggesting that neuronal apoptosis requires the participation of cellular protein synthesis activity and therefore might represent an active form of cell death.