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http://www.plosone.org/article/info%...l.pone.0002444
Research Article


Computational Systems Analysis of Dopamine Metabolism
Zhen Qi1,2,3, Gary W. Miller2,3, Eberhard O. Voit1*

1 Department of Biomedical Engineering, Georgia Institute of Technology and Emory University Medical School, Atlanta, Georgia, United States of America2 Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America3 Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia, United States of America

Abstract
A prominent feature of Parkinson's disease (PD) is the loss of dopamine in the striatum, and many therapeutic interventions for the disease are aimed at restoring dopamine signaling. Dopamine signaling includes the synthesis, storage, release, and recycling of dopamine in the presynaptic terminal and activation of pre- and post-synaptic receptors and various downstream signaling cascades. As an aid that might facilitate our understanding of dopamine dynamics in the pathogenesis and treatment in PD, we have begun to merge currently available information and expert knowledge regarding presynaptic dopamine homeostasis into a computational model, following the guidelines of biochemical systems theory. After subjecting our model to mathematical diagnosis and analysis, we made direct comparisons between model predictions and experimental observations and found that the model exhibited a high degree of predictive capacity with respect to genetic and pharmacological changes in gene expression or function. Our results suggest potential approaches to restoring the dopamine imbalance and the associated generation of oxidative stress. While the proposed model of dopamine metabolism is preliminary, future extensions and refinements may eventually serve as an in silico platform for prescreening potential therapeutics, identifying immediate side effects, screening for biomarkers, and assessing the impact of risk factors of the disease.