Caspase Dependent Programmed Cell Death

Research within the past decade has shown the importance of cysteine proteases that cleave after aspartate residues (caspases) in PCD (Cohen 1997; Earnshaw et al. 1999). Two caspase-dependent PCD pathways, the intrinsic (mitochondrial) pathway

  1. 4.3 Autophagy involves the formation of cytoplasmic autophagosomes. These photomicrographs show mouse hepatocytes in a mouse not given food for 24 h. (a) shows the cytoplasm of a hepatocyte with normal mitochondria but with vacuolar structures in the cytoplasm (arrowheads). (b) through (e) show autophagosomes containing recognizable cytoplasmic structures, whereas (f) shows a lysosome with unidentifiable electron-dense material (from Uchiyama et al. 2008, with permission from Springer)
  2. 4.3 Autophagy involves the formation of cytoplasmic autophagosomes. These photomicrographs show mouse hepatocytes in a mouse not given food for 24 h. (a) shows the cytoplasm of a hepatocyte with normal mitochondria but with vacuolar structures in the cytoplasm (arrowheads). (b) through (e) show autophagosomes containing recognizable cytoplasmic structures, whereas (f) shows a lysosome with unidentifiable electron-dense material (from Uchiyama et al. 2008, with permission from Springer)

involving caspase-9 (casp-9) activation, and the extrinsic (death-receptor) pathway involving caspase-8 (casp-8) activation, both result in activation of caspase-3 (casp-3), the principal executioner caspase. Following an apoptotic stimulus with mitochondrial membrane permeabilization, cytochrome c (cyt c) translocates to the cytosol, where it forms the "apoptosome," together with apoptotic protease activating factor-1

(Apaf-1) and dATP, which cleaves casp-9, activating it (Liu et al. 1996, 1997; Zou et al. 1997). Active casp-9 cleaves casp-3 (Li et al. 1997), and the cleaved (active) casp-3 translocates to nuclei, activating caspase-activated DNase (CAD)/DNA fragmentation factor 40 (DFF40) by cleaving inhibitor of CAD (ICAD)/DNA fragmentation factor 45 (DFF45) (Liu et al. 1997, 1998; Enari et al. 1998; Sakahira et al. 1998). CAD/DFF40 then cleaves double-stranded DNA at internucleosomal sites, producing 180 base pair fragments that have a ladder-like appearance on electrophoresed DNA agarose gels (DNA laddering) (Liu et al. 1997, 1998; Enari et al. 1998; Sakahira et al. 1998).

In the CNS morphological apoptosis, both naturally occurring and that induced by an acute insult, occurs during the neonatal period, becoming undetectable in older rats (Ikonomidou et al. 1999; Liu et al. 2004) (Fig. 4.4). Exceptions in the adult rat have been observed (Sloviter et al. 1993, 1996). It has also been shown that casp-3 activation is age-dependent in cerebral ischemia, occurring during the neonatal period and becoming negligible in the adult rat (Hu et al. 2000; Liu et al. 2004) (Fig. 4.5). Thus, casp-3 activation occurs in morphologically apoptotic neurons in the neonatal brain. Earlier studies have shown casp-3 activation in adult rodents following cerebral ischemia (Hara et al. 1997; Chen et al. 1998) and focal status epilepticus (SE) (Henshall et al. 2000), or activation of upstream casp-8 and casp-9 in focal SE (Henshall et al. 2001a, b), but none of the studies showed morphological neuronal apoptosis, and the preponderance of subsequent studies, to be discussed in the next subsection, have pointed to caspase-independent PCD pathways in excito-toxic neuronal death, of which cerebral ischemia and SE are examples.

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