Parkinson's disease: dopaminergic nerve cell model is consistent with experimental finding of increased extracellular transport of α-synuclein

Background: Parkinson's disease is an age-related disease whose pathogenesis is not completely known. Animal models exist for investigating the disease but not all results can be easily transferred to humans. Therefore, mathematical or probabilistic models for the human disease are to be constructed in silico in order to predict specific processes within a cell, such as the dopamine metabolism and transport processes in a neuron. Results: We present a Systems Biology Markup Language (SBML) model of a whole dopaminergic nerve cell consisting of 139 reactions and 111 metabolites which includes, among others, the dopamine metabolism and transport, oxidative stress, aggregation of alpha-synuclein (alpha SYN), lysosomal and proteasomal degradation, and mitophagy. The predictive power of the model was investigated using flux balance analysis for the identification of steady model states. To this end, we performed six experiments: (i) investigation of the normal cell behavior, (ii) increase of O-2, (iii) increase of ATP, (iv) influence of neurotoxins, (v) increase of alpha SYN in the cell, and (vi) increase of dopamine synthesis. The SBML model is available in the BioModels database with identifier MODEL1302200000. Conclusion: It is possible to simulate the normal behavior of an in vivo nerve cell with the developed model. We show that the model is sensitive for neurotoxins and oxidative stress. Further, an increased level of alpha SYN induces apoptosis and an increased flux of alpha SYN to the extracellular space was observed.