FIGURE 3.

ROS and other stimuli induce DNA damage subsequently leading to the hyperactivation of PARP-1 and PARylation (Andrabi et al., 2008; Narne et al., 2017). Excessive PAR polymers translocate from the nucleus to mitochondria and induce AIF release from mitochondria. AIF recruits MIF into the nucleus and causes chromatinolysis and large-size DNA fragmentation (Wang et al., 2011; Wang et al., 2016). In AD and PD, excessive glutamate activates N-Methyl-D-aspartic acid (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that induce Ca²⁺ influx and NOS activation, leading to generation of NO and ONOO−, which can potentiate DNA damage and trigger parthanatos (Fatokun et al., 2013). Activation of cAMP/PKA axis promotes phosphorylation of mitochondrial PARP-1, thereby promoting parthanatos (Brunyanszki et al., 2014). Epac activates Rap and H-Ras, and upregulates PARP expression by inhibiting its cleavage (Grandoch et al., 2009b). These mechanisms highlight the role of cAMP signaling in promoting parthanatos via both PKA and Epac. For further details, see text.