Parkinson's disease (PD) results primarily from striatal dopamine (DA) insufficiency and degeneration of dopaminergic neurons within the substantia nigra pars compacta. The cause of PD still remains unknown and the mainstay of therapy is DA replacement. But as PD progresses, drug-related side effects emerge as well as disabling symptoms that are not responsive to the treatment. This means that many patients must endure crippling symptoms for many years, severely impacting their quality of life. For this reason, therapies aimed at stopping the continual loss of DA neurons and restoring function is needed to slow or halt disease progression. We have demonstrated that lentiviral delivery of glial derived neurotrophic factor (GDNF) can be used to protect DA function in an animal model of PD. The neurotrophic factor neublastin/artemin (NeuB) is a recently identified compound of the GDNF family that seems to be at leastas potent as GDNF to protect, enhance sprouting and production of DA in nigral cells in animal models of PD. This project proposes to determine (1) if delivery of NeuB by lentiviral vectors will be an effective protective agent in the unilateral MPTP animal model of early PD and, (2) if NeuB can rescue dopaminergic function in an established animal model of PD. As we propose to use similar methods to the ones that we used to analyze GDNF neuroprotection in MPTP-treated animals, we will be able to compare the neurotrophic properties of both factors. If these preclinical experiments are successful, they may provide an innovative alternative strategy to prevent the progression of the disease and restore dopaminergic function in parkinsonian patients.