Advances in neuronal cell death 2007

"Death Hath so Many Doors to Let Out Life." - John Fletcher & Francis Beaumont. While life and death are binary events, there are many different pathways for cells to die. We are just coming to the realization that there is more to cell death than apoptosis and necrosis, which implies that our understanding of cell death in the brain is severely restricted. Until we understand the primary pathways that result in cell death after ischemia, we will not be able to define new and effective therapies. Several advances this year are predictive of future studies. When AIF was first identified, it was thought that AIF mediated a very specific and restricted form of caspase-independent cell death. We are now finding that AIF belongs to the growing family of mitochondrial death effectors and that many different signaling events can lead to AIF release. AIF can be released as a commitment point to cell death, but it can also be released later in the cell death cycle. Nuclear AIF is a promiscuous marker for cell death; therefore, it is important to determine whether AIF translocation is a primary causal event in the cell death process by blocking AIF translocation. Additional work is necessary to fully understand the role of AIF in neuronal cell death. There is a growing number of caspase-independent cell death effectors being identified in the brain, but a lot of work is required in order to understand which are primary causal events, toward which therapeutics might be targeted, and which are secondary and perhaps less important events. Along these lines, PAR signaling appears to be an important primary event that would be amenable for therapeutic development. Lastly, autophagy is likely to be a very fruitful frontier for understanding the response of the brain to stress and injury. Cell death due to autophagy may turn out to be one of the more important cell death signaling events in the brain and is a relatively untapped area of research.