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Mathematical Models of Dopamine Metabolism in Parkinson’s Disease

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Systems Biology of Parkinson's Disease

Abstract

As discussed in Chap. 1 and elsewhere in this volume, a feature of Parkinson’s disease (PD) is a reduction in dopamine concentration in the striatum, caused by progressive loss of dopamine neurons in the substantia nigra pars compacta. Dopamine is a crucial neurotransmitter that is involved in numerous physiological functions, and its role in PD has been studied extensively. However, the dynamics of dopamine in situ are not fully understood because it is affected by a large number of metabolites, other biological components, and an ill-characterized spectrum of environmental and genetic factors. This chapter describes the state of the art in mathematical models of dopamine metabolism and signal transduction. First, the topology of the dopamine pathway is reviewed. Second, the construction of two types of models is discussed. The first of these models targets dopamine metabolism in the presynaptic terminal, while the second describes dopamine-based signal transduction at the synapse and signal integration in the postsynaptic target neurons. The construction phase of symbolic models is followed by numerical configurations based on data. The resulting parameterized models are then compared with experimental and clinical observations as a means of testing their validity and predictive power. The best model is utilized to analyze ill-understood aspects of the role of dopamine in PD and to identify critical molecules and processes that might be potential therapeutical targets. Simulations of drugs targeting these sites are presented and evaluated with respect to their benefits, possible side effects, and downstream effects of perturbations in dopamine dynamics.

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Acknowledgments

This work was supported by a grant from the National Institutes of Health (P01-ES016731, G.W.M., PI) and a grant from the University Systems of Georgia (E.O.V., PI). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the sponsoring institutions.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Georgia Institute of Technology, 313 Ferst Drive, Atlanta, GA, 30332, USA

    Zhen Qi & Eberhard O. Voit

  2. Center for Neurodegenerative Disease, Emory University, 201 Dowman Drive, Atlanta, GA, 30322, USA

    Zhen Qi & Gary W. Miller

  3. Integrative BioSystems Institute, Georgia Institute of Technology, Atlanta, GA, 30332, USA

    Zhen Qi & Eberhard O. Voit

  4. Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA

    Gary W. Miller

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  1. Zhen Qi
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Correspondence to Zhen Qi .

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Editors and Affiliations

  1. , Hamilton Institute, National University of Ireland, Maynooth, Maynooth, Kildare, Ireland

    Peter Wellstead

  2. Ecole Polytechnique de Montreal, C.P. 6079, Succ. Centre-ville, Montreal, H3C 3A7, Québec, Canada

    Mathieu Cloutier

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Qi, Z., Miller, G.W., Voit, E.O. (2012). Mathematical Models of Dopamine Metabolism in Parkinson’s Disease. In: Wellstead, P., Cloutier, M. (eds) Systems Biology of Parkinson's Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3411-5_8

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