Generation and analysis of candidate genes from substantia nigra

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The goal of this project is to investigate differential gene expression in the substantia nigra in order to generate candidate genes for Parkinson's Disease (PD), a heritable neurological disorder characterized by pathological degeneration of substantia nigra. The investigators hypothesize that degeneration is associated with an altered pattern of gene expression in this tissue; therefore, genes whose expression in this tissue is significantly up-or down-regulated in affected individuals constitute good candidate genes for PD and related disorders. Additional candidate genes will be identified as those genes that are expressed in the normal substantia nigra at a higher level than in other regions of normal human brains. Serial Analysis of Gene Expression (SAGE) is a powerful technique that allows quantitative determination of all transcripts present in a given tissue by cloning and sequencing large numbers of unique 13-base pair tags associated with each gene. Dr. Vance and his collaborators plan to use SAGE to compare the population of genes expressed in substantia nigra isolated from three different sources: normal control individuals, individuals affected with Lewy body positive PD, and individuals affected with FTDP, a Lewy body negative neurodegenerative disease also characterized by gliosis of the substantia nigra. This last group of samples will allow the investigators to control for the confounding effects of under-representation of neurons in the PD substantia nigra. Genes that are under- or over-expressed in the substantia nigra in the disease-state will be considered potential candidate genes, as will any genes expressed specifically in the normal substantia nigra. These candidate genes will be tested for association with PD in Project I using sub-based association analysis among patients with idiopathic PD as outlined in Project I. This double screen-differential expression in the appropriate tissues, as well as statistical association with disease-will be a very powerful mechanism for selecting candidate genes.