Programmed Cell Death and the Control of Cell Survival: Lessons from the Nervous System

Abstract

During the development of the vertebrate nervous system, up to 50 percent or more of many types of neurons normally die soon after they form synaptic connections with their target cells. This massive cell death is thought to reflect the failure of these neurons to obtain adequate amounts of specific neurotrophic factors that are produced by the target cells and that are required for the neurons to survive. This neurotrophic strategy for the regulation of neuronal numbers may be only one example of a general mechanism that helps to regulate the numbers of many other vertebrate cell types, which also require signals from other cells to survive. These survival signals seem to act by suppressing an intrinsic cell suicide program, the protein components of which are apparently expressed constitutively in most cell types.

Tanshinone IIA attenuates the cerebral ischemic injury-induced increase in levels of GFAP and of caspases-3 and -8

“…After transient occlusion of the middle cerebral artery followed by reperfusion, the number of apoptotic cells in the striatum and cortex of rats was directly proportional to the duration of ischemia (Raff et al, 1993). The mechanism of apoptosis involves a signal transduction process by which intracellular protein is degraded by a family of cysteine-dependent aspartate-directed proteases (caspases).…”

Cloning and Expression of a Rat Brain Interleukin-1β-Converting Enzyme (ICE)-Related Protease (IRP) and Its Possible Role in Apoptosis of Cultured Cerebellar Granule Neurons

“…The precise nature of this fatal selection, however, remains a mystery. Previous studies suggest that the death of these neurons occurs via apoptosis, a physiological mechanism by which a cell dies via transcriptional and translational activation of an intrinsic cell death or suicide program (Raff et al, 1993;Wood et al, 1993). Several lines of evidence also suggest that apoptotic cell death not only is required for normal CNS development but is involved in pathological neuronal death, which occurs in neurodegenerative disorders such as Alzheimer's disease (Cotman and Anderson, 1995;LaFerla et al, 1995;Lassmann et al, 1995), in which neuronal cell loss is a prominent feature.…”

“…However, a rather dramatic downregulation of IRP mRNA expression was observed in these same brain regions by PND 10. It is tempting to speculate that this dramatic developmental change in IRP expression coincides with the rather substantial loss of neurons, which is known to occur via apoptosis during brain development (Raff et al, 1993). However, the relationship between IRP mRNA expression, its translation to protein, and functional protease activity are as yet unclear, and further work will be necessary to substantiate a role for IRP in normal brain development.…”

Caspases: the executioners of apoptosis

“…During embryonic development, Nedd2 is expressed at relatively high levels in various tissues, including the central nervous system, liver, kidneys and lungs [57]. Both the kidney and central nervous system are associated with high levels of programmed cell death during development [59]. Nedd2 is also expressed to varying extents in several adult tissues, including post-mitotic neurons [57].…”