Constraint-Based Modelling of Bioenergetic Differences between Synaptic and Non-Synaptic Components of Dopaminergic Neurons in Parkinson's Disease

Xi Luo¹Diana C El Assal²Yanjun Liu¹Samira Ranjbar³Ronan MT Fleming^1*

• ¹Department of Medicine, School of Medicine, University of Galway, Galway, County Galway, Ireland
• ²New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
• ³University of Galway, Galway, Ireland

Emerging evidence suggests that different metabolic characteristics, particularly bioenergetic differences, between the synaptic terminal and soma may contribute to the selective vulnerability of dopaminergic neurons in patients with Parkinson’s disease (PD). To investigate the metabolic differences, we generated four thermodynamically flux-consistent metabolic models representing the synaptic and non-synaptic (somatic) components under both control and PD conditions. Bioenergetic analyses across all models predicted that oxidative phosphorylation plays a significant role under lower energy demand, while glycolysis predominates when energy demand exceeded mitochondrial constraints. The synaptic PD model predicted a lower mitochondrial energy contribution and higher sensitivity to Complex I inhibition compared to the non-synaptic PD model, highlighting the bioenergetic differences between these neuronal components. Altered fluxes in several exchanged metabolites in two PD models were consistent with variations in metabolite concentrations observed in the cerebrospinal fluid of PD patients. Specifically, both PD models predicted reduced uptake of lysine and lactate, indicating coordinated metabolic processes between these components. In contrast, decreased methionine and urea uptake was exclusively predicted in the synaptic PD model, while decreased histidine and glyceric acid uptake was exclusive to the non-synaptic PD model, suggesting distinct potential metabolic patterns in these regions. Furthermore, increased flux of the mitochondrial ornithine transaminase reaction (ORNTArm), which converts oxoglutaric acid and ornithine into glutamate-5-semialdehyde and glutamate, was predicted to rescue bioenergetic failure and improve metabolite exchanges for both the synaptic and non-synaptic PD models. Further research is needed to validate these dysfunction mechanisms across different components of dopaminergic neurons and to explore targeted therapeutic strategies for PD patients.