INVOLVEMENT OF THE PROTEASOME IN THE PROGRAMMED CELL-DEATH OF NGF-DEPRIVED SYMPATHETIC NEURONS

Sympathetic neurons undergo programmed cell death (PCD) upon deprivati on of nerve growth factor (NGF). PCD of neurons is blocked by inhibito rs of the interleukin-1 beta converting enzyme (ICE)/Ced3-like cystein e protease, indicating involvement of this class of proteases in the c ell death programme. Here we demonstrate that the proteolytic activiti es of the proteasome are also essential in PCD of neurons. Nanomolar c oncentrations of several proteasome inhibitors, including the highly s elective inhibitor lactacystin, not only prolonged survival of NGF-dep rived neurons but also prevented processing of poly(ADP-ribose) polyme rase which is known to be cleaved by an ICE/Ced-3 family member during PCD. These results demonstrate that the proteasome is a key regulator of neuronal PCD and that, within this process, it is involved upstrea m of proteases of the ICE/Ced-3 family. This order of events was confi rmed in macrophages where lactacystin inhibited the proteolytic activa tion of precursor ICE and the subsequent generation of active interleu kin-1 beta.