Neuronal Death The Final Pathway

The nature, time course, and molecular causes of cell death in neurodegenerative diseases and their relations to basic processes discussed above are still a matter of controversy. Based on distinct morphologic criteria and biochemical features, three major mechanisms of neuronal demise are discussed: apoptosis, a specific form of gene-directed programmed cell death (PCD); (oncotic) necrosis, a passive killing of the cell; and autophagic degeneration (256,257). Morphologically, apoptotic cell death is characterized by chromatin condensation (pyknosis), nuclear fragmentation, cell shrinkage, and plasma membrane blabbing. Eventually, the cell breaks into small membrane-surrounded fragments (apoptotic bodies), which are cleared by phagocytosis in vivo without inciting an inflammatory response (258), phagocytotic activity being balanced by positive and negative signals (259). Apoptosis can occur locally, without damaging healthy adjacent cells. This is in contrast to necrotic cell death, which exhibits rapid cell swelling and subsequent rupture of the plasma membrane that, due to an inflammatory response, usually induces substantial secondary cell damage in the surrounding tissue. Many of the morphological differences between apoptotic and necrotic processes are thought to be a consequence of the action of cysteine proteases, and recent studies suggest that caspase and calpain functions in cell death are bridging the gap between apoptosis and necrosis (260,260a). Autophagic cell death, a normal physiological process active in both homeostasis and atrophy, probably representing a failure of neuroprotective mechanisms (261), is characterized by the formation of numerous autophagic vacuoles, endocytosis, enlargement of the GA as a source of lysosomes providing hydrolytic enzymes for the vacuolization of the ER, and moderate condensation of nuclear chromatin that may ultimately leave the pyknotic nuclei and is destroyed by autophagosomes (262). Neuronal cell death may exhibit morphologic features of autophagy or necrosis, which differ from that of canonical apoptosis (263) or autophagic vacuolation can precede apoptotic cell death, which argues against the clear distinction between apoptotic and autophagic cell death (264). Another cell death process is excitotoxic neurodegeneration that has been described either as a necrotic or apoptotic process (265). Increasing evidence suggests that the regulation of neuronal cell death is complex, utilizing multiple pathways that are depending on the damaging insult, such as Ca and intracellular energy levels, mitochon-drial dysfunction, withdrawal of neurotrophic support, glutamate receptor stimulation, OS, NO release, etc., each demonstrating specificity of function, regulation and pathway involvement, influenced by subtle differences among cell phenotypes (257,266-268).

Cellular energy reserves play a crucial role in the major forms of cell death, with apoptosis favored under conditions with mild insults and preserved ATP levels; necrosis induced by spontaneous insults, such as ischemia, trauma, or excitoxicity, with depletion of ATP and persistent depolarization of the mitochondrial membrane potential, opening of the PTP, release of cytochrome c, followed by depletion of energy reserves (267). Mitochondria are essential in controling specific apoptotic pathways including release of a number of apoptosis-inducing factors or death receptors, activators of the caspase/calpain, Bcl-2 and p53 families, and the mitogen-activated protein kinase pathway that finally induce proteolysis of specific cellular substructures and consequently amplify the death signal cascade (257,267-270).

There are myriads of reasons and ways for a neuron to die, among which apoptosis is a specific form that is processed in two major signaling pathways, the TNF-receptor-mediated (extrinsic) and the mitochondria-based (intrinsic) cell pathways, with several avenues of cross-talk between them (271). The nature, time course, and molecular causes of cell death in human disease and their relation to basic processes discussed above are still a matter of discussion. Similar death signaling pathways might be activated in neurodegenerative disorders by abnormal subcellular protein stuctures, cytoplasmic or nuclear fibrillar inclusions, mitochondrial dysfunction and energy deficits, as well as by neurotrophin deficiencies and other factors. The key molecular players of apoptosis,

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Fig. 5. Overview of apoptotic signaling through the receptor-mediated ("extrinsic") and mitochondria-based ("intrinsic") pathways.

the importance of the caspase cascade via interaction with different death domains, and the role of effective caspase driving the execution of the cell death program are summarized in Fig. 5.

Although the various molecular players in apoptotic cell death are becoming increasingly well known, whether or not they are involved or may interact with one another in the neuronal cell death cascade in various neurodegenerative processes is a matter of discussion (257,268,271-277).

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