Evolution of apoptosis-like programmed cell death in unicellular protozoan parasites

Apoptosis-like programmed cell death (PCD) has been described in multiple taxa of unicellular protists, including the protozoan parasites Plasmodium [1,2], Trypanosoma [3,4] and Leishmania [5]. PCD in protists appears to share some morphological features with apoptosis in multicellular organisms, including chromosomal condensation, nuclear DNA fragmentation, cell shrinkage, loss of mitochondrial membrane potential, formation of apoptotic bodies, and the externalisation of phosphatidylserine [2,4]. However, without knowledge of the molecular mechanisms involved in the apoptosis-like PCD of parasites, it is unclear which markers are expected to be observed and under which conditions. Apoptosis in multicellular organisms is initiated in response to a wide variety of stress factors, ranging from cell senescence to oxidative damage [6,7], and is executed by the activation of the caspase family of cysteine proteases [8]. Although apoptosis-like PCD in unicellular organisms can also be initiated by a variety of stresses [4,5,9] and the morphological features (diagnostics) are similar across multicellular and unicellular taxa [2,4,9], much of the molecular machinery of unicellular organisms appears to differ. For example, canonical caspases are encoded only in the Metazoan genomes [10-12].This mixture of similarities in the basic features of apoptosis but key differences in the underlying mechanisms across taxa has resulted in controversy over whether apoptosis, or a form thereof, is actually the process being observed in protozoan parasites. This controversy must be resolved as the possibility of manipulating cell death pathways in parasites may offer a new avenue for disease control. Empirical tests of gene function have made progress in identifying some the molecules involved in executing apoptosis, and bioinformatics offers a complimentary approach to integrate these results across taxa. Bioinformatic comparisons of multicellular model systems, protozoan parasites, and