What can trigger the onset of Parkinson's disease – A modeling study based on a compartmental model of α-synuclein transport and aggregation in neurons

• A minimal model describing events leading to the onset of PD is developed.
• Accumulation of α-syn is unlikely without failure of α-syn degradation machinery.
• Neurons may be especially vulnerable to a failure to degrade misfolded α-syn.
• α-syn accumulation is likely to start in the synaptic compartment.
• The obtained results may explain the dying-back pattern often observed in PD.

The aim of this paper is to develop a minimal model describing events leading to the onset of Parkinson's disease (PD). The model accounts for α-synuclein (α-syn) production in the soma, transport toward the synapse, misfolding, and aggregation. The production and aggregation of polymeric α-syn is simulated using a minimalistic 2-step Finke–Watzky model. We utilized the developed model to analyze what changes in a healthy neuron are likely to lead to the onset of α-syn aggregation. We checked the effects of interruption of α-syn transport toward the synapse, entry of misfolded (infectious) α-syn into the somatic and synaptic compartments, increasing the rate of α-syn synthesis in the soma, and failure of α-syn degradation machinery. Our model suggests that failure of α-syn degradation machinery is probably the most likely cause for the onset of α-syn aggregation leading to PD.

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