A convoluted way to die.

The current picture of sympathetic neuronal cell death pathway is as follows (Figure 1(Figure 1). Upon removal of NGF, neurons induce at least four proteins that may play critical roles in apoptotic signal transduction: BIM, DP5/Hrk, and two transcription factors of the AP-1 family—c-Jun and c-Fos. Because c-Jun is necessary but maybe not sufficient to induce BIM expression, c-Jun and another factor(s) may act together to regulate the expression of BIM, DP5/Hrk, or other BH3-like proteins. c-Fos is unlikely to be involved as its induction is a very late event. The mechanism by which neurons activate c-Jun is at least partially through JNK. Activation of JNK is critical for the development of competence-to-die, which may act by releasing the cytoplasmic “brake” for caspase activation. Upregulated BIM, DP5/Hrk, etc., may act to neutralize the neuronal antiapoptotic arsenals such as BCL-2 and BCL-xL, thereby facilitating BAX aggregation and mitochondrial insertion. Thus, the neuronal apoptotic pathway is built in such a way to assure that only when both proapoptotic signaling pathways are activated is the green light to caspase activation turned on to be swiftly followed by neuronal death.The existing information showed that certain apoptotic pathways, such as death receptor–induced cell death, are incredibly direct: there are very few signal transduction steps that go from an extracellular death signal to the activation of caspases, which results in the quick final demise of a cell. In contrast, neurons seem to have evolved an intricate and convoluted way to die. Why? One reasonable answer is that most cell types in our body are programmed to live for a short time and are turned over rather quickly. Therefore, they are highly disposable—from the organism point of view, it is much better to eliminate a compromised cell than try to mend it. Neurons, on the other hand, are much more precious—throughout our lives, we maintain roughly the same set of neurons as when we are born, if we are fortunate enough to live free of neurodegenerative diseases. Furthermore, mature neurons are nonproliferative and, therefore, it is unlikely that a defective neuron may overproliferate and turn cancerous. Thus, the organism seems to have adapted an entirely different policy for neurons: to keep them alive any way it can.What does this complicated neuronal apoptosis pathway tell us about the therapeutic opportunity of neurodegenerative diseases? Many studies have demonstrated that apoptotic mechanisms contribute to both acute and chronic neurodegenerative diseases (Yuan and Yankner, 2000xYuan, J and Yankner, B.A. Nature. 2000; 407: 802–809Crossref | PubMed | Scopus (1267)See all References(Yuan and Yankner, 2000). Inhibition of caspase activation has shown beneficial effects in a number of animal models of neurodegenerative models. Convoluted neuronal cell death pathways may be good news to us: as multiple controlling points in the neuronal death pathways may provide additional flexibility in choosing the best therapeutic points. One word of caution, however, is that it remains to be seen whether activation of a single neuronal cell death pathway, which is not sufficient for neurons to die in short-term culture, can be ignored in the long term and whether a “half-dead” neuron can be fully functional. Nevertheless, we have made tremendous progress in understanding the mechanisms of neuronal cell death in the last decade, and this growing body of information will very likely help us to develop novel treatments of neurodegenerative diseases in the next decade.