One of the current major hypotheses for the pathogenesis of Parkinson's Disease is that it is due to programmed cell death (PCD). This hypotheses proposes that the genetic programs which mediate PCD, which occur normally during development, become re-activated inappropriately in adulthood, leading to the spontaneous degeneration of neurons. The plausibility of this hypothesis is supported by a number of observations made in our laboratory. We have shown for the first time that PCD with the morphology of apoptosis occurs during normal postnatal development of dopamine neurons. We have shown for the first time that PCD with the morphology of apoptosis occurs during normal postnatal development of dopamine neurons. We have also shown that this death event is regulated; it can be induced by early striatal target lesion. We have shown that PCD can be induced in one important model of parkinsonism, that caused by the neurotoxin 6-hydroxydopamine. Our primary goal now is to define the molecular basis of PCD in phenotypically-defined dopamine neurons in the substantia nigra of living animals. In the setting of developmental cell death and the striatal target injury model we have shown that the immediately early gene c-jun and its kinase JNK, the proteolytic enzyme caspase-3, and the cyclin dependent kinase cdk5 are expressed in association with PCD in dopamine neurons temporally and spatially at a cellular level. In this proposal we will examine three themes related to the role these molecules play in PCD in dopamine neurons: (1) Is their expression a general feature of PCD in these neurons? (2) Do they play a functional role in mediating cell death? (3) How does expression of these molecules interrelate, i.e., what is the sequences of molecular events? The new knowledge gained by the investigations planned in this proposal will make possible a more incisive analysis of the role of PCD in PD. With the identification of the molecules which play a role in PCD in these neurons, it will become possible to make a systematic analysis of the expression of biochemical markers of PCD in PD brain; up to novel investigations have been limited to simple morphologic assessments. Identification of the molecules which mediate PCD in the PD brain will ultimately make possible novel therapeutic approaches aimed at preventing the progressive neuronal degeneration characteristic of this disease.