Key note lecture: toward a mechanistic taxonomy for cell death programs

Abstract

Background and purpose: Programmed cell death (pcd) plays a critical role in the development of the nervous system, as well as in its response to insult. Both anti-pcd and pro-pcd modulators play prominent roles in development and disease, including ischemic cerebrovascular disease. The purpose of this article is therefore to review the basics of programmed cell death.

Methods: There have been over 100 000 scientific and clinical publications on the topic of programmed cell death and its most well known form, apoptosis. The principles emerging from these studies are reviewed here.

Results: Programmed cell death is a form of cell death in which the cell plays an active role in its own demise. Apoptosis is the most well-defined form of pcd, but recent studies have begun to characterize an alternative program, autophagic cell death. In addition, there appear to be programmatic cell deaths that do not fit the criteria for either apoptosis or autophagic cell death, arguing that additional programs may also be available to cells.

Conclusions: Constructing a mechanistic taxonomy of all forms of pcd--based on inhibitors, activators, and identified biochemical pathways involved in each form of pcd--should offer new insight into cell deaths associated with cerebrovascular disease and other diseases, and ultimately offer new therapeutic approaches.

Figure 1

Comparison of different cell death programs. Note the difference in morphology present in each form, as well as the differences in biochemical mediators, inducers, and inhibitors. At the current time, only apoptosis and autophagic pcd are generally accepted as being legitimate forms of programmed cell death; however, ongoing research should reveal which of the additional candidates represent novel pathways of pcd. Photomicrographs are from the following references, used with permission: apoptosis, autophagic cell death, paraptosis, calcium-mediated pcd, AIF/PARP-dependent pcd, and oncosis (from Bredesen et al, with permission).

Figure 2

Intrinsic and extrinsic pathways of apoptosis (from Bredesen et al, with permission).