Contribution of p53-Dependent Caspase Activation to Neuronal Cell Death Declines with Neuronal Maturation

Abstract

Caspases play a pivotal role in neuronal cell death during development and after trophic factor withdrawal. However, the mechanisms regulating caspase activity and the role played by caspase activation in response to neuronal injury is poorly understood. The tumor suppressor gene p53 has been implicated in the loss of neuronal viability caused by excitotoxic and DNA damaging agents. In the present study we determined if p53-mediated neuronal cell death required caspase activation. DNA damage increased caspase activity in both cultured embryonic telencephalic and postnatal cortical neurons in a p53-dependent manner. Caspase inhibitors protected embryonic telencephalic neurons, but not postnatal cortical neurons, from DNA damage-induced cell death as measured by direct cell counting and annexin V staining. In marked contrast to the caspase inhibitors, an inhibitor of the DNA repair enzyme, poly(ADP-ribose) polymerase, conferred significant protection from genotoxic and excitotoxic cell death on postnatal cortical neurons but had no effect on embryonic neurons. Glutamate-mediated excitotoxicity in postnatal neurons was not associated with measurable changes in caspase activity, consistent with the failure of caspase inhibitors to prevent cell death under these conditions. Moreover, adenovirus-mediated overexpression of p53 killed embryonic and postnatal neurons without activating caspases. Thus, p53-mediated neuronal cell death may occur via both caspase-dependent and caspase-independent pathways. These results demonstrate that p53 is required for caspase activation in response to some forms of neuronal injury. However, the relative importance of caspase activation in neurons depends on the developmental status of the cell and the specific nature of the death stimulus.

Caspase-independent death of meiotic and postmeiotic cells overexpressing p53: calpain involvement

“…27 In the same way, RARaÀ/À mice exhibit caspase-independent spermatid loss. 28 Late differentiating male germ cells share similarities with various postmitotic/terminally differentiating models of caspase-independent cell death: p53-expressing or NMDAtreated neurons, 17,18 ischemic mature brain, 29 light-injured mature photoreceptor cells 19 or differentiating PC12 cells. 30 So in terminally maturing cells, calpain activation bypasses an inhibition or a block in the caspase pathway generally related to a decrease in apoptotic effectors like Apaf1 or caspase-3.…”

“…These ubiquitous enzymes are involved (i) in testicular cell loss in ischemia/reperfusion models, 6 and (ii) in several models of postmitotic, differentiating cell death. [17][18][19] Calpain 2 mRNAs were observed at all differentiation stages of normal spermatogenesis without any modification in transgenic cells (Figure 7a). By contrast, calpain 1 mRNAs were only detected in normal SP cells and spermatocytes II.…”

Involvement of p53 and Fas/CD95 in murine neural progenitor cell response to ionizing irradiation

“…However, Eizenberg et al (1996) propose that p53 has an importance during brain development in directing progenitors toward either apoptosis or differentiation. p53 plays a key role in genotoxic stress-mediated apoptosis and G1 cell cycle arrest in many cell types including neural cells (Slack et al, 1996;Jordan et al, 1997;Komarova et al, 1997;Levine, 1997;Herzog et al, 1998;Xiang et al, 1998;Johnson et al, 1999;Chao et al, 2000;Chong et al, 2000;Chow et al, 2000;Miller et al, 2000;Bargonetti and Manfredi, 2002). Several reports have shown that, in vivo, g-irradiation preferentially induces apoptosis in undifferentiated multipotent precursors localized in subependyma zone, subventricular zone and subgranular zone of dentate gyrus of the brain of adult mice (Herzog et al, 1998;Chow et al, 2000;Lee et al, 2001;Uberti et al, 2001).…”

The role of p53 in neuronal cell death

“…Recent studies indeed demonstrated that p53 is required for caspase activation in response to genotoxic stress. 69,96,129,140 These findings suggest that some forms of neuronal injury invoke a common pathway involving signal transduction through p53, Bax, mitochondrial dysfunction, cytochrome c release and caspase activation. However, other forms of injury have been shown to induce neuronal cell death by stimulating Bax translocation and caspase activation independently of p53.…”

“…Caspase-3 activation is required for p53-dependent cell death in cerebellar granule neurons in response to ionizing radiation 96 consistent with results obtained in nonneuronal cells. 139,142 ± 144 However, specific peptide inhibitors of caspases (zVAD-fmk, zDEVD-fmk and BAF) did not protect hippocampal and cortical neurons from p53-dependent cell death induced by radiation, 71 glutamate 72 or camptothecin-treatment 140 when the neuronal cultures were established from postnatal animals as opposed to embryos. In addition, adenovirus-mediated overexpression of p53 promoted neuronal cell death but did not induce caspase activity in postnatal cortical neurons.…”