'Men are but worms:': neuronal cell death in C-elegans and vertebrates

Awarding the 2002 Nobel Prize in Physiology or Medicine to Sydney Brenner, H Robert Horvitz, and John E Sulston for 'their discoveries concerning the genetic regulation of organ development and programmed cell death (PCD)' highlights the significant contribution that the study of experimental organisms, such as the nematode Caenorhabditis elegans, has made to our understanding of human physiology and pathophysiology. Their studies of lineage determination in worms established the 'central dogma' of apoptosis: The BH3-only protein EGL-1 is induced in cells destined to die, interacts with the BCL-2-like inhibitor CED-9, displacing the adaptor CED-4, which then promotes activation of the caspase CED-3. The vast majority of cells undergoing PCD during development in C. elegans, as in vertebrates, are neurons. Accordingly, the genetic regulation of apoptosis is strikingly similar in nematode and vertebrate neurons. This review summarizes these similarities - and the important differences - in the molecular mechanisms responsible for neuronal PCD in C. elegans and vertebrates, and examines the implications that our understanding of physiological neuronal apoptosis may have for the diagnosis and treatment of acute and chronic human neurodegenerative disorders.