Activation of caspase-3 in developmental models of programmed cell death in neurons of the substantia nigra

Programmed cell death has been proposed to play a role in the death of neur ons in acute and chronic degenerative neurologic disease. There is now evid ence that the caspases, a family of cysteine proteases, mediate programmed cell death in various cells. In neurons, caspase-3 (CPP32/Yama/apopain), in particular, has been proposed to play a role. We examined the expression o f caspase-3 in three models of programmed cell death affecting neurons of t he substantia nigra in the rat: natural developmental neuron death and indu ced developmental death following either striatal target injury with quinol inic acid or dopamine terminal lesion with intrastriatal injection of 6-hyd roxydopamine, Using an antibody to the large (p17) subunit of activated cas pase-3, we have found that activated enzyme is expressed in apoptotic profi les in all models. Increased p17 immunostaining correlated with increased e nzyme activity. The subcellular distribution of activated caspase-3 differe d among the models: In natural cell death and the target injury model, it w as strictly nuclear, whereas in the toxin model, it was also cytoplasmic. W e conclude that p17 immunostaining is a useful marker for programmed cell d eath in neurons of the substantia nigra.