Lysosomal Dependent Cell Death and Parthanatos: Two Developmental Alternative Cell Death Pathway in Drosophila

Programmed cell death (PCD) is an intracellular genetic program that essentially exists in all metazoan organisms. Apoptosis is the most abundant form of PCD, executed by the activation of proteases called caspases, however, emerging evidence indicates the existence of several caspase-independent alternative cell death (ACD) pathways. Given that cancer cells are highly resistant to apoptosis, exploring alternative pathways to kill these cells might be of tremendous therapeutic value. We have discovered two distinct developmental paradigms of ACDs in Drosophila, germ cell death (GCD) and primordial germ cell death (PGC death), corresponding to the non-physiological ACD pathways termed lysosomal dependent cell death (LDCD) and parthanatos, respectively.

GCD - We have previously shown that during normal spermatogenesis in the adult testis, 20-30% of the newly emerging male germ cells undergo GCD. This cell death pathway is independent of the main effector caspases, and requires some lysosomal hydrolases and mitochondrial enzymes. We now demonstrate that GCD is regulated by the Hippo-Warts-Yorkie signaling pathway emanating in the surrounding somatic cells.

PGC death - During embryonic specification of the germline progenitor cells, called PGCs, 1/3 of them undergo cell death.We confirmed previous studies showing that PGC death is caspase independent. We then show that PGC death is triggered by the lysosomal nuclease, DNase II, and mediated by the Poly(ADP-ribose) polymerase-1 (PARP-1) and the mitochondrial Apoptosis Inducing Factor (AIF). Furthermore, we demonstrate that PGC death is executed downstream of the DNA damage response pathway.