The goal of this proposal is to begin to identify tile role of the dendrite in l-methyl-4-phenylpyridine (MPP+)-mediated toxicity in dopaminergic neurons as a model of neurodegeneration in Parkinson?s disease (PD). The overall hypothesis is that MPP+ disrupts dendrite function early in the cell death pathway, and that neurotrophic factors such as BDNF, NT-4/5, and/or GDNF may prevent these early dendritic changes, and thus, cell death. The expression and intracellular trafficking of specific candidate and novel mRNAs will be evaluated using expression profiling. Samples will be collected from isolated neurites and cell bodies of individual dopaminergic neurons under various experimental conditions of toxin exposure and growth factor treatment at times which correspond to early degeneration. Active genes will then be further analyzed for changes in abundance and subcellular distribution of their specific proteins by a novel proteomics methodology which was recently developed in this lab. These studies will begin to explore the molecular mechanisms of dendrite involvement in neurodegeneration and neuroprotection using cutting-edge technologies in a system that is highly applicable to PD.
