Parkinson's disease (PD) is a brain disorder caused by progressive loss of the brain chemical dopamine. Patients with Parkinson's disease are treated with levodopa (L-DOPA), a precursor of dopamine. However, L-DOPA therapy has disabling side effects. Most patients on L-DOPA treatment are eventually afflicted with motor fluctuations and abnormal, involuntary movements known as dyskinesias. L-DOPA-induced dyskinesias can become more disabling than Parkinson's disease itself. In severe cases, neurosurgical lesioning of basal ganglia nuclei such as the thalamus, pallidum or subthalamic nucleus is needed to improve Parkinson's disease and to minimize L-DOPA dosage. The proposal is based on the hypothesis that L-DOPA treatment in Parkinson's disease, and L-DOPA-induced dyskinesia, are accompanied by unique patterns of gene expression in the putamen. By comparing the gene expression patterns of dyskinesia to non-dyskinesia, we may find the critical factors responsible for the development of dyskinesia, or responsible for preventing the development of dyskinesia. Specific therapies could then be devised that could be co-administered with L-DOPA to prevent dyskinesias. We propose to investigate the molecular systems that are altered in L-DOPA-induced dyskinesia, and to find the 'molecular signature' of dyskinesia. We will study gene expression patterns in the post mortem putamen in Parkinson's disease in response to L-DOPA treatment (PD;
Specific Aim 1) and in response to L-DOPA-induced dyskinesia (Specific Aim 2), and compare it to a rat model of L-DOPA-induced dyskinesia (Specific Aim 3). The role of five candidate genes for the development of, or compensation for, dyskinesia will then be examined in the rat model (Specific Aim 4). In a gene array experiment we have already collected data from the rat model of dyskinesia and assembled lists of candidate genes from these data. The lists of genes will be cross-referenced with the findings in the human putamen to determine five most likely candidates to be tested in the rat model. Hypothesis testing will be combined with computer programs that can find interesting new, unanticipated patterns of gene regulation, and help to formulate new hypotheses. The post mortem samples provide us with direct access to the human condition, while the animal model provides us with an experimental system that can be tightly controlled and that permits functional analyses and hypothesis-testing. Together they can lead the way toward new treatments for dyskinesia. ? ?
