Regulation of neuronal cell death and differentiation by NGF and IAP family members
Nerve growth factor (NGF) and other neurotrophins were identified because of their trophic role for distinct populations of neurons in the peripheral nervous system. We know that neuronal cell death is regulated by a genetically encoded programme, called
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Nerve growth factor (NGF) and other neurotrophins were identified because of their trophic role for distinct populations of neurons in the peripheral nervous system . We know that neuronal cell death is regulated by a genetically encoded programme, called apoptosis, that is conserved from worms to humans. Dysregulation of this programme is thought to contribute to neurodegenerative diseases which are characterized by the loss of neurons. This article will review recent findings about the motoneuron disease spinal muscular atrophy (SMA). Two closely linked candidate genes for SMA, the SMN (survival motor neuron) gene and the NAIP (neuronal apoptosis inhibitory protein) gene have been reported. The SMN protein forms a complex with several other proteins and this complex containing SMN plays a critical role in the assembly of spliceosomes and in pre-mRNA splicing. NAIP, cIAP1 (inhibitor of apoptosis-I), c-IAP2, X-lAP and survivin comprise the mammalian inhibitor of apoptosis family. Its members can protect mammalian cells from apoptosis induced by a variety of stimuli. Some of the lAP molecules have been shown to interact both with cell signalling molecules and with specific caspases but details concerning their cellular role are only incompletely characterized. Summary.
Neuronal survival
Neurons may undergo cell death after exposition to distinct stimuli at different developmental stages. Many of the early descriptions of naturally occuring cell death during development concerned the nervous system (Glticksmann, 1951). Most classes of neurons are generated in excess during development, and up to 50% of these neurons die shortly afterwards when their neurites have made contact with the target tissues (Oppenheim, 1991). Neuronal cell death is now known to be executed by an endogenous cell suicide program called programmed cell death or apoptosis that is evolutionary conserved among all animals. It is of crucial importance not only during embryonic and neural development but also in maintenance of the nervous system and in pathological situations such as stroke and degenerative diseases (Jacobson
P. Riederer et al. (eds.), Advances in Research on Neurodegeneration © Springer-Verlag Wien 2000
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R. Gotz
et al., 1997). In humans, extensive neuronal death is observed in neurodegenerative diseases and after stroke and trauma. Diseases such as amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease are mostly sporadic, and the causal events have not yet been identified. However, a small fraction of these diseases are inherited and there are examples of a genetic disease with the phenotype of neuronal degeneration. One such example is the specific loss of motoneurons in the spinal cord of children with spinal muscular atrophy (see below) . Neuronal survival is promoted by specific growth factors , for example neurotrophins, which act on distinct neuronal populations by binding to specific cell surface receptors which in turn activates a number of enzymes and genes (Frade and Barde, 1998). Removal of
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