In the third year of this grant, we are about to complete one experiment, and have initiated another. In Experiment 1, we assessed whether lentiviral delivery of the antiapoptotic gene Bcl-2 could prevent the functional and structural consequences of MPTP toxicity in nonhuman primates. Our preliminary data indicate that lentiviral delivery of Bcl2 did not influence MPTP-mediated motor deficits as measured on a clinical rating scale and an operant hand reach task, likely because Bcl-2 may not be able to preserve striatal dopaminergic innervation. We are currently evaluating Neurochemically and morphologically whether lenti- Bcl2 provided neuroprotection at the level of the substantia nigra. We have just initiated a second experiment in which aged monkeys are assessed for levodopa-induced dyskinesias and given a fluorodopa PET scan. They then receive lenti-GDNF under the control of the tetracycline promoter. Three months following lenti-GDNF, they are again assessed for levodopa-induced dyskinesias and given a fluorodopa PET scan. Then half of the aged monkeys receive tetracycline to shut of the GDNF expression in vivo. Monkeys are assessed for levodopa- induced dyskinesias and given a fluorodopa PET scan 3 and 6 months later. This study will determine whether we can control gene expression in vivo and make gene therapy safe for clinical use.