Recent advances on neuronal caspases in development and neurodegeneration

In view of a large and growing literature, this overview emphasizes recent advances in neuronal caspases and their role in cell death. To provide hist orical perspective, morphology and methods are surveyed with emphasis on ea rly studies on interleukin converting enzyme (ICE) as a prototype for ident ifying zymogen subunits. The unexpected homology of ICE (caspase-1) to Caen orhabditis elegans death gene CED-3 provided early clues linking caspases t o programmed cell death, and led later to discovery of bcl-2 proteins (CED- 9 homologs) and 'apoptosis associated factors' (Apafs). Availability of sub strates, inhibitors, and cDNAs led to identification of up to 16 caspases a s a new superfamily of unique cysteine proteinases targeting Asp groups. Th ose acting as putative death effecters dismantle neurons by catabolism of p roteins essential for survival. Caspases degrade amyloid precursor protein (APP), presenilins (PS1, PS2), tau, and huntingtin, raising questions on th eir role in neurodegeneration. Brain contains 'inhibitors of apoptosis prot eins' (IAPs) survivin and NAIP associated also with some neuronal disorders . Apoptotic stress in neurons initiates a chain of events leading to activati on of distal caspases by pathways that remain to be fully mapped. Neuronal caspases play multiple roles for initiation and execution of cell death, fo r morphogenesis, and in nonmitotic neurons for homeostasis. Recent studies focus on cytochrome c as pivotal in mediating conversion of procaspase-9 as a major initiator for apoptosis. Identifying signaling pathways and relate d events paves the way to design useful therapeutic remedies to prevent neu ronal loss in disease or aging. (C) 1999 Elsevier Science Ltd. All rights r eserved.