Parkinson's disease (PD) is a progressive neurological disorder characterized by degeneration of the dopaminergic neurons of the substantia nigra. Although the majority of the cases appear sporadically, a familiar form of PD has been identified that is caused by mutations in the gene encoding the a-synuclein protein. a-Synuclein is expressed widely in the nervous system and is normally present as an unfolded protein. In PD brains, however, it has been shown to be a major component of the Lewy bodies and neurites, i.e., the pathological hallmarks of the disease, suggesting that a-Synuclein plays a central role in the pathological processes that leads to dopamine neuron degeneration. Current research, therefore, is focused on the biochemical interactions and protein modifications that lead to aggregation and fibrillation of a-synuclein, and how altered a-synuclein act to impair dopamine neuron function and survival. Previous efforts to generate a-synuclein pathology have been focused on transgenic mice overexpressing human a-synuclein. These mice exhibit a-synuclein accumulation in neurons throughout the nervous system, however, with very little or no PD-like pathology in the nigrostriatal dopamine neurons. We have recently developed a new model of PD using a recombinant AAV vector to express human a-synuclein in the nigrostriatal dopamine neurons in adult rats and pre-clinical models. These animals develop pathological a-synuclein-positive inclusions in the nigral dopamine cell bodies and their axonal projections, accompanied by progressive degeneration of dopaminergic neurons and their axonal projections, and development of Parkinson-like motor imparments. The goal of the present project is, first, to characterize this new PD model in detail, in both rats, mice and primates, and correlate the pathological changes with a detailed analysis of the accompanying sensorimotor behavioral deficits. Second, to study the interactions between a-synuclein and other cellular stress mechanisms, such as increased oxidative damage, impaired dopamine handling, and pharmacological manipulation of doppamine synthesis, storage and breakdown. And, third, to explore ways to block a-synuclein aggregation, and thus modify the disease process, by using different truncated forms of a-synuclein that are known to exhibit altered fibrillogenic properties. In parallel, we will examine the potential of GDNF, one of the most potent neurotrophic factors for nigral dopamine neurons, as a neuroprotector against a-synuclein- indused neurodegeneration.