Parkinson's disease results from a loss of dopamine neurons in brain areas that control body movement. However, the cause of this loss is unknown and thus it has been difficult to develop rational strategies to prevent it from occurring. Recently it was discovered that mutations in the gene for alpha-synuclein are associated with some cases of familial parkinsonism. Thus, alpha-synuclein may provide clues regarding the pathogenesis of this disease. We have developed cellular models to study the effects of alterations in alpha-synuclein and the mechanisms by which trophic factors can rescue dopamine neurons from toxic insults. Using cell lines and primary neuronal cultures from the brain region containing the dopamine neurons, we will explore the hypothesis that normal levels of alpha-synuclein expression increase the capacity of dopamine neurons to resist the neurotoxic effects of a variety of agents, whereas reduced levels of alpha-synuclein or mutant alpha-synuclein increases neuronal vulnerability. We then will explore the ability of glial cell line derived neurotrophic factor (GDNF) to protect dopamine neurons against the cell death associated with alpha-synuclein abnormalities. The main focus will be on signaling cascades known to be involved in cell survival and cell death, specifically the PI3'K/Akt and Ras/Map Kinase pathways.