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"Proteins that have been shown to be abnormal in individuals with ALS. ^Proteins that have been shown to be unchanged in ALS.

"Proteins that have been shown to be abnormal in individuals with ALS. ^Proteins that have been shown to be unchanged in ALS.

neurons. The elimination of these supernumerary neurons in the developing nervous system occurs by normal programmed neurodegeneration at specific times. This normal neurodegeneration is thought to be important for matching the size of neuronal groups to the size of their targets (other groups of neurons to which they are connected by axons and nerve terminal synapses) as well as to their own synaptic inputs from other regions. This developmental neuronal death (particularly of spinal and sympathetic ganglion neurons and motor neurons) is thought to be partially controlled by the supply of sustaining neurotrophic factors that are synthesized by the target axon-associated glial cells or by the input regions. Thus, an insufficient supply of neurotrophic molecules triggers an apoptotic process within interconnected groups of neurons by PCD.

Apoptosis is regulated by specific molecules within cells (Table VI). Several genes that regulate apoptosis were originally identified in a nematode worm. Homologous genes have been identified in mammalian cells. The molecular mechanisms for apoptosis involve the participation of at least three groups of proteins that are made from three different gene families. One set of proteins is the caspase family of cysteine-containing, aspartate-specific proteases (14 members have been identified to date). A second group includes the death-promoting and death-suppressing proteins in the Bcl-2 family (e.g., Bcl-2, Bcl-xL, Bax, Bak, Bad, Boo). A third group of proteins is designated as the inhibitor of apoptosis protein (IAP) family.

Caspases exist as dormant proenzymes in healthy cells and are activated through regulated proteolysis. These proteins function in the execution phase of apoptosis with ''initiator'' caspases activating ''effec tor'' caspases, which subsequently cleave a variety of proteins, thereby causing the molecular and structural changes of apoptosis. Once activated, caspases act on nuclear proteins, cytoskeletal proteins, or cytosolic proteins. Two different caspase cascades mediate PCD. One pathway involves the regulated release of cytochrome c from mitochondria that promotes the activation of caspase-9 through Apaf-1 and then caspase-3 activation. Another pathway is initiated by the activation ofcell-surface death receptors, including Fas and tumor necrosis factor receptor, leading to caspase-8 activation, which in turn cleaves and activates downstream caspases such as caspase-3, -6, and -7.

Apoptosis regulation by the bcl-2 protooncogene family is a very complex and exciting process (Table VI). Of these genes, bcl-2 and bcl-xL are antiapoptotic (death-suppressing), whereas bax, bcl-xS, bad, bak, and bik are proapoptotic (death-promoting). Membership into the family of Bcl-2-related proteins is defined by homology domains within their amino acid sequences. These domains function in the interactions (i.e., binding) between members. Bcl-2 family members exist as monomers (single proteins) that form homo-dimers (two of the same proteins bound together), heterodimers (two different proteins bound together), and higher order multimers (more than two interacting proteins). For example, Bax forms homodimers or forms heterodimers with either Bcl-2 or Bcl-xL. When Bax is present in excess, it antagonizes the antiapop-totic activity of Bcl-2. The formation of Bax homodimers promotes apoptosis, whereas Bax heterodimerization with either Bcl-2 or Bcl-xL blocks apoptosis. Thus, the complex steady-state array of protein-protein interactions among members of the

Figure 10 Neurodegeneration in the form of apoptosis is important for the normal development of the nervous system. By electron microscopy this naturally occurring programmed cell death has very characteristic features. (A) In the developing rat striatum, degenerating neurons in the early stages of apoptosis are characterized by chromatin condensation into crescentic caps (arrowhead) abutting the nuclear envelope and into round aggregates (asterisk). The surrounding cytoplasm condenses (as indicated by the uniformly dark staining), although most of the mitochondria remain intact. Scale bar = 2.5 mm. (B) As apoptosis progresses, major changes occur in the nucleus and cytoplasm. The chromatin packaging into dense round clumps (asterisk) becomes more advanced, and the integrity of the nuclear envelope is lost. The cytoplasm becomes more condensed and the mitochondria become damaged. Astrocytic processes (a) begin to surround the degenerating cell. Scale bar = 3.0 mm. (C) At end stage apoptosis, fragments of cells consist of round packages of chromatin (asterisk) surrounded by condensed cytoplasm. These apoptotic fragments are engulfed by astrocytic processes (a). Scale bar = 4.0 mm.

Figure 10 Neurodegeneration in the form of apoptosis is important for the normal development of the nervous system. By electron microscopy this naturally occurring programmed cell death has very characteristic features. (A) In the developing rat striatum, degenerating neurons in the early stages of apoptosis are characterized by chromatin condensation into crescentic caps (arrowhead) abutting the nuclear envelope and into round aggregates (asterisk). The surrounding cytoplasm condenses (as indicated by the uniformly dark staining), although most of the mitochondria remain intact. Scale bar = 2.5 mm. (B) As apoptosis progresses, major changes occur in the nucleus and cytoplasm. The chromatin packaging into dense round clumps (asterisk) becomes more advanced, and the integrity of the nuclear envelope is lost. The cytoplasm becomes more condensed and the mitochondria become damaged. Astrocytic processes (a) begin to surround the degenerating cell. Scale bar = 3.0 mm. (C) At end stage apoptosis, fragments of cells consist of round packages of chromatin (asterisk) surrounded by condensed cytoplasm. These apoptotic fragments are engulfed by astrocytic processes (a). Scale bar = 4.0 mm.

Bcl-2 family functions in dictating whether a cell lives or dies by apoptosis.

Cell death is also regulated by the IAP (inhibitor of apoptosis protein) family (Table VI). This family includes X-chromosome-linked IAP, IAP1, IAP2, and NAIP (neuronal apoptosis inhibitory protein). Survival motor neuron is another apoptosis inhibitory protein. The primary mechanism identified by which IAPs suppress apoptosis is the prevention of proteo-lytic processing of specific caspases. It appears that procaspase-9 is the major target of IAPs. However, IAPs do not prevent caspase-8-induced proteolytic activation of procaspase-3. IAPs can also block apoptosis by reciprocal interactions with the nuclear transcription factor NFkB. NAIP is abnormal in infants and children with spinal muscular atrophy (Table II).

The regulation of PCD in the mammalian nervous system by caspases and bcl-2 family members has been substantiated by using transgenic mouse technology and neuronal culture systems. In mice, deficiencies in the genes for caspase-3 and caspase-9 result in perinatal death and cerebral malformations, possibly caused by reduced PCD during brain development. Inhibition of caspase-1 and caspase-2 blocks the apoptosis of cultured dorsal root and sympathetic ganglion neurons when deprived of the neurotrophin nerve growth factor; furthermore, inhibition of cas-pase-1 arrests the PCD of motor neurons in cell culture resulting from neurotrophic factor deprivation and in the nervous system during the period of naturally occurring cell death. Mice that overexpress the bcl-2 gene or have the bax gene eliminated fail to exhibit normal PCD of neurons in some nervous system regions, whereas bcl-2-deficient mice show progressive neurodegeneration after the period of PCD.

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