Parthanatos steps out of the shadows of cell death and into the developmental spotlight

About a dozen mechanistically distinct caspase-independent alternative cell death pathways (ACDs) have been described in different experimental systems in vitro. ACDs have received much attention in recent years because of their possible involvement in the pathogenesis of a variety of diseases. While there are compelling reasons for excitement, troubling questions regarding the in vivo biology remain, as it is inevitable that studies in cell culture could not reproduce the complexity of the in vivo reality, which could even lead to inaccurate notions. A major reason for the slow progress in this area is that extremely few physiological paradigms of non-apoptotic cell death pathways that have been described in metazoan model organisms. We have been investigating a developmental cell death, which eliminates one third of the primordial germ cells (PGCs) during early embryogenesis in Drosophila. Intriguingly, PGC death was suggested to occur independently of the proapoptotic reaper family genes, and was unaffected by overexpression of the effector caspase inhibitor protein p35. Nonetheless, the underlying signaling pathways and mechanisms governing PGC death have remained unclear for more than a decade.

I will report our unpublished results showing that although the dying PGCs undergo cell death with morphological features reminiscent of apoptosis, PGC death is not mediated by the apoptotic caspases, but rather by a few lysosomal hydrolases. Furthermore, I will present data strongly suggesting that PGC death constitutes the first developmental paradigm of parthanatos, mediated by the lysosomes and executed downstream of the DNA damage response pathway.