Neuronal programmed cell death without caspases

Abstract

The proper development of the vertebrate nervous system is accompanied by a massive loss of neurons. This is to remove neurons that make improper connections or no connections at all, and therefore to match the number of neurons with their targets. The removal of unwanted neurons is not a chaotic, but a highly organized, controlled and reproducible process that is achieved by programmed cell death (PCD). It has been known for some time now that the central players in apoptosis-like PCD are members of a specific family of cysteine proteases termed caspases. Two distinct classes of caspase, the ‘initiator’ (or ‘upstream’, such as caspase-9) and ‘effector’ (or ‘downstream’, such as caspase-3) cleave specific substrates in the nucleus and cytoplasm. The caspase substrates fall into two groups – those that are activated by caspases (and contribute to cell death, such as the ICAD–CAD nuclease complex) and those that are destroyed by caspases (to prevent them from fulfilling their normal cellular function, such as PARP or DNA–PK).