Core components of the apoptotic machinery. The likelihood that a neuron undergoes apoptosis is determined by the interplay of the tightly interlinked apoptotic machinery, many components of which are highly conserved between species. The critical, and often terminal, step in programmed cell death is the proteolytic activation of the executor caspases (such as caspase 3, 6, 7) by the initiator caspases (i.e., caspase 8, 9, and 10; Riedl and Salvesen, 2007). In mammalian cells, initiation of the executor caspases is regulated by two distinct protein cascades: the intrinsic pathway, also known as the mitochondrial pathway, and the extrinsic pathway. The intrinsic pathway integrates a number of intra- and extracellular signal modalities, such as redox state (for example, the reactive oxygen species; Franklin, 2011), DNA damage (Sperka et al., 2012), ER stress (Puthalakath et al., 2007) and growth factor deprivation (Deckwerth et al., 1998; Putcha et al., 2003; Bredesen et al., 2005), or activation of the p75NTR neurotrophin receptor by pro-neurotrophins (Nykjaer et al., 2005). The stressors converge onto pro- and anti-apoptotic members of the Bcl-2 protein family (for example: BCL-2, BCL-X_l, BAX, and tBID; Youle and Strasser, 2008). These proteins regulate the release of cytochrome c from mitochondria, which activates the initiator caspase 9 through Apaf1 (Riedl and Salvesen, 2007). The extrinsic pathway links activation of ligand-bound death receptors (such as Fas/CD95 and TNFR) to the initiator caspase 8 and 10, through formation of the death-inducing signaling complex (DISC; LeBlanc and Ashkenazi, 2003; Peter and Krammer, 2003). Together with additional regulatory elements (including the Inhibitors of apoptosis proteins [IAP]; Vaux and Silke, 2005) and cFLIP (Scaffidi et al., 1999; Wang et al., 2005), the apoptotic machinery forms a balance that determines the propensity of the neuron to undergo apoptosis.