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The overall goal of the Center is to understand the molecular and transcriptional events that contribute to the pathophysiology of Parkinson's disease. The Center consists of investigators who use a diverse set of techniques to approach these questions - from yeast genetics, models and pharmacology to studies in human cultured neurons and human brain samples. The Center is made up of four projects and three cores. Project 1 is lead by Dr. Brad Hyman and focuses on molecular chaperones in Lewy body diseases. The hypotheses are that alpha-synuclein is misfolded and associated with molecular chaperones in human Lewy body diseases and that molecular chaperones decrease the aggregation and misfolding in vitro and in vivo. FRET, FLIM, CHIP and bimolecular fluorescence techniques are used in culture and viral vectors for in vivo studies. Project 2 is lead by Dr. Susan Lindquist and uses yeast as a model for understanding alpha-synuclein biology. The project examines the quality control mechanisms that influence alpha-synuclein misfolding and aggregation. The two primary quality control mechanisms are molecular chaperones and protein degradation. Alpha-synuclein is toxic in yeast and assays can be constructed that allow genetic, chemical and peptide screens to identify suppressors of toxicity. Genes, peptides and chemicals that are identified in yeast can then be tested in Drosophila and mammalian models of alpha-synuclein toxicity. Project 3 is lead by Dr. Ann Graybiel and is examining the neurophysiology and neurobiology of the nigrostriatal system. The project focuses on the effects of alpha-synuclein toxicity on striatal based learning. These studies are being carried out using in vivo electrophysiology with tetrodes in awake behaving parkinsonian rodents. The second part of the study is to identify gene transcription changes in striosomes and matrix of animals models of PD in which the animals have levodopa-induced dyskinesias. These latter studies are being carried out using laser capture microdissection. RT-PCR and Q-PCR is being used to validate the changes seen in gene transciption assays. Finally Western blots of candidate proteins are being used to see whether the levels of functional proteins are affected. Project 4 is lead by Dr. Anne Young and is examining the gene transcription changes that occur in Parkinson's and Lewy body diseases. Using laser capture microdissection, nigral neurons from PD and control cases were examined. Gene expression levels from DLB, PD and controls were examined and altered genes were validated with quantitative RT-PCR. Projects are being done in collaboration with Projects 1 and 3. Core A is the Administrative Core. Core B is the Clinical Core. Core B supports the training of two Udall fellows a year as well as data management for the clinical database and neuropathology. Patients are referred to participate in specific research projects and brains are collected at death for clinical pathological correlations and to supply brain tissue for research investigators. Core C is the Bioinformatics Core. Core C serves all projects in the analysis of genetic and microarray data. It has created a public database for this information.

Last updated August 13, 2007