Computational Systems Analysis of Dopamine Metabolism

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.

A pragmatic approach to biochemical systems theory applied to an α-synuclein-based model of Parkinson's disease

“…Other approaches that would be well suited for comparisons to the model include gene expression analysis techniques such as Northern blots and RNA expression microarrays, and data from other biochemical models. Papers produced by the Voit group at Emory University and the Gorin group at UC Davis offer data from dynamic modeling studies on dopamine metabolism and ␣-synuclein aggregation (Raichur et al, 2006;Kaushik et al, 2007;Qi et al, 2008). Still, the literature largely lacks modeling data relevant to PD.…”

Resumos

“…Evidências de danos induzidos pelo estresse oxidativo são encontradas em modelos farmacológicos como o da reserpina (BILSKA et al, 2007;FORNSTEDT;CARLSSON, 1989 VOIT, 2008). Os danos neuronais causados pelo estresse oxidativo podem promover tanto alterações motoras quanto cognitivas (SANTOS et al 2013;TEIXEIRA et al, 2009).…”

Biochemical Systems Theory: A Review

“…Dopamine is a crucial neurotransmitter in the reward system of mammals, including humans, and changes in dopamine concentrations can lead to Parkinson's disease, schizophrenia, sleep disorder, and attention de�cit�hyperactivity disorder [44,174,[602][603][604][605][606][607][608][609], (see also [175,[610][611][612]). e work of Qi's group contains models for the presynapse, which is a nerve ending in the midbrain where dopamine is produced, as well as the postsynapse in the forebrain, where dopamine signals are interpreted.…”