Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease trigger neuronal cell death through endogenous suicide pathways. Surprisingly, although the cell death itself may occur relatively late in the course of the degenerative process, the mediators of the underlying cell-death pathways have shown promise as potential therapeutic targets.

Thank Heaven! The crisis - the danger, is past, and the lingering illness, is over at last - and the fever called "Living" is conquered at last. - from For Annie, by Edgar Allan Poe

Programmed cell death (PCD) has a critical role in the development of the nervous system, and both anti-PCD and pro-PCD modulators feature prominently in the establishment of neural architecture. It has been 100 years since the first description of developmental neuronal-cell death, and more than 50 years since Levi-Montalcini showed that such physiological cell death is inhibited by soluble factors such as nerve growth factor. Dysregulation of cell-death programmes features in developmental and neoplastic disorders of the nervous system, and there is increasing evidence to suggest that such dysregulation may also occur in neurodegenerative, infectious, traumatic, ischaemic, metabolic and demyelinating disorders.

In 1964, Lockshin and his colleagues introduced the term programmed cell death to describe the apparently predetermined pattern by which specific cells die during insect development. In 1966, it was shown that this process requires protein synthesis, at least in some cases, indicating that it is the result of an active cellular suicide process. Then, in 1972, John Kerr and his colleagues coined the term apoptosis to describe a morphologically relatively uniform set of cell deaths seen in many different situations, from development to insult response to cell turnover.

Although PCD has often been equated with apoptosis, non-apoptotic forms also exist, and neurodegenerative conditions such as Huntington's disease, amyotrophic lateral sclerosis (ALS) and ischaemia show cell deaths that do not fulfil the criteria for apoptosis.

Classical developmental studies support the view that at least three different forms of PCD are distinguishable: type I, also known as nuclear or apoptotic; type II, also known as autophagic; and type III, also known as cytoplasmic. These occur reproducibly in specific nuclei and with specific frequencies, at particular times of nervous-system development. But these cell-death pathways may also be activated by various insults, such as DNA damage or the accumulation of misfolded proteins.

Neurodegenerative diseases are associated with a number of insults that may trigger PCD: misfolded proteins, reactive oxygen and nitrogen species, mitochondrial-complex inhibition, calcium entry, excitotoxicity, trophic-factor withdrawal, and death-receptor activation to name a few. In some cases, however, deaths occur that do not fit neatly into any of the three classes of PCD, and these more controversial forms of death are also discussed below.