SELECTIVE VULNERABILITY OF DOPAMINE NEURONS IN PARKINSON'S DISEASE

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Not all dopamine neurons are equally vulnerable to degeneration in idiopathic Parkinson's disease (PD). "Nigrosomes" of substantia nigra pars compacts are most vulnerable with nigral matrix, retrorubral area and ventral tegmental area next in vulnerability while hypothalamic and periaqueductal gray neurons are resistant to the degenerative process. This project will test the hypothesis that the dopamine neurons most vulnerable to parkinsonian degeneration differ from relatively resistant neurons by having higher concentrations of molecules that make them vulnerable to degeneration (alpha-synuclein, recently found to be mutated in some PD families and to be present in Lewy bodies; parkin, recently found to be mutated in autosomal recessive-juvenile parkinsonism; torsinA, the dopamine neuron chaperonin that is mutated in early onset torsion dystonia; or dopamine transporters). The newly developed double-label in situ hybridization histochemistry and antisense RNA techniques will be used to compare the gene expression rates of these compounds in the different subgroups of dopamine neurons in control brains and in the brains of persons dying with PD. In collaboration with projects 1, 2 and 4, ligand binding studies will be done to study dopamine and GABA function in the basal ganglia of mice transgenic for the alpha-synuclein and torsinA mutations. These experiments are important for testing the overall hypothesis that specific molecules are important to PD pathogenesis since they will link these molecules directly to the effected neurons while generalized evidence for changes in their expression in PD might be a result from rather a cause of the disease process.