The goal of this project is to identify and evaluate candidate susceptibility genes for Parkinson disease (PD) using a mulfifactorial process we have termed """"""""genomic convergence."""""""" This approach utilizes a number of different kinds of data, including genomic linkage analysis, gene expression profiles in PD patients as well as controls, biological activity of candidate genes, molecular analysis, and family-based association analysis. Several different brain tissues are severely affected in PD patients: the anterior olfactory nucleus is one of the first tissues to be affected in PD, the substantia nigra shows dramatic loss of dopaminergic neurons over the course of disease, and imaging studies of the putamen show defects in dopamine and nicotinic acetylcholine receptor binding. In this project, we will measure the level of gene expression in these tissues in order to identify candidate susceptibility genes for PD. We will also use laser capture microscopy to identify candidate genes by measuring gene expression in three different cell types within the substantia nigra: the dopaminergic neurons, non-pigmented neurons, and astroglial cells. Together with Project III, we will examine gene expression in cybrid cultures. Differentially expressed genes will then be prioritized in a variety of ways. First, we will identify those that map to regions of PD linkage. Second, we will evaluate the biological activity of genes to find those that are consistent with known metabolic defects in PD. This process of convergence will greatly reduce the number of genes that must be evaluated. We will then identify single nucleotide polymorphisms (SNPs) within or nearby these prioritized genes. Taqman assays will be developed for each of these SNPs, and they will be transferred to Core C for genotyping and Project I for analysis. Genes that show association with PD or interactions with other genes or the environment will be evaluated further for their role in PD.
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