Neuronal Death Outcomes 331 General Considerations

It is widely accepted that apoptosis may represent the predominant neuronal death phenotype occurring during synaptogenesis (Oppenheim et al. 2001). By contrast, the importance of classical apoptosis in the adult nervous system is still under debate. According to some studies, apoptosis is down regulated (at least under physiological conditions) due to a differentiation-associated reduction in Apaf-1 expression and increased efficacy of IAPs (inhibitors of apoptosis proteins) (Wright et al. 2004). Moreover, the over-expression of IAPs confers neuroprotection in vivo (Perrelet et al. 2000) whereas neuronal IAP (NAIP)-deleted mice display increased vulnerability to kainic acid injury (Holcik et al. 2000). Besides these genetic factors, inhibition of caspases can result from cross-inhibition by other proteases activated simultaneously (Chua et al. 2000), silencing by viral proteins in the course of infection (Strasser et al. 2000), nitrative/oxidative stress (Leist et al. 1999), and energy depletion (Leist et al. 1997). Neurons are highly sensitive to the latter, since they depend entirely on the aerobic metabolism of glucose, which generates ROS as by-products (see section "Increase in intracellular Ca2+ concentration").

At this stage, there exists reasonable evidence arguing that, in physiological conditions, apoptosis is inhibited in adult neurons, whereas in pathological conditions it can be re-activated. Predominance of alternative (i.e. caspase-independent) PCD outcomes such as autophagic and apoptosis-like cell death programmes is currently emerging as a consensus [for review, see Krantic et al. (2007) and Krantic et al. (2005)]. Concerning these alternative PCD phenotypes, there is so far no explicit evidence for the involvement of AIF-mediated programmed necrosis in neurons, which would be similar to that described in MEFs (Moubarak et al. 2007). However, given that AIF has been involved in neuronal death along the apoptosis-like pathway, it is important to re-examine the relevant neuronal PCDs. Thus, some of neuronal PCD phenotypes, originally considered as apoptosis-like, might turn to be programmed necrosis. This can be the case, for example, of peroxide-treated cerebella granule neurons (CGN) dying by AIF-mediated apoptosis-like PCD, where inhibition of mPT by cyclosporin A provides a partial protection against cell death (Hans et al. 2005), thus revealing a putative programmed necrosis component of the cell death process triggered by peroxide. Indeed, as already discussed in the section "Decreased ATP production/energetic failure," inhibition of PT by targeting CypD pharmacologically with cyclosporin A prevents (programmed?) necrosis. Distinguishing apoptosis-like PCD from programmed necrosis is crucial not only from a theoretical (taxonomic) point of view but also from a practical standpoint, since this knowledge might orient future neuroprotective strategies more accurately.

Clear distinction between accidental and AIF-mediated programmed necrosis requires a careful re-examination of the underlying pathways. It can be done, for example, by testing the sensitivity of the death process to cyclosporin A, to help distinguish those processes that are programmatic in nature, hence allowing for therapeutic intervention.

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