Dopamine dysregulation in Parkinson's Disease

Parkinson's disease (PD), characterized by the absence of dopamine in the striatum[1], is caused by the death of the substantia nigra pars compacta dopamine (SNcDA) neurons in the midbrain. The loss of these autonomously pacemaking[2] neurons is attributed to irreparable damage due to a dysregulation cascade starting from excess cytosolic dopamine and its decomposition into its aldehyde[3]. However, it is unresolved if dopamine dysregulation in SNcDA neurons themselves is the cause of PD or if it is a mere symptom.

Here, we applied a recent theory of metabolic spikes[4] to SNcDA neurons, to account for their autonomous pacemaking activity. According to the metabolic spike hypothesis, neurons, presumably in anticipation of synaptic inputs, keep their ATP levels at a maximum such that they are ATP-surplus/ADP-scarce. When cellular energy consumption is low, the ADP levels are low, consequently ATP production stalls in their mitochondria and forms toxic Reactive Oxygen Species(ROS)[5]. Under these circumstances, `metabolic spikes’ are self-initiated to restore ATP production and preempt ROS toxicity. We propose that in SNcDA neurons such metabolic spikes are diminished and can account for both - the decreased dopamine tone in the striatum and the subsequent cytosolic dopamine dysregulation.

We model this in two cellular domains. Firstly, in the SNcDA’s soma, a metabolism-coupled leaky integrate and fire model senses cellular ROS levels and initiates metabolic spikes. Here, we identified four categories of defects, that may cause loss of metabolic spikes that remarkably correspond to many known risk factors for PD. Secondly, at the presynaptic terminals, we modeled a mass-action model that can account for the release, reuptake, synthesis, and degradation of dopamine. We show that lowered metabolic spikes (autonomous activity) at the soma can promote dopamine degradation into a disruptive aldehyde (DOPAL) at the presynaptic terminals, increasing cellular maintenance, and ultimately cell death.

Using a multi-spatiotemporal scale model that spans from single molecules to network level and from the millisecond spike events to cellular loss in decades, we demonstrate the nuance of the disease progression and the vulnerabilities that lead to PD. Our theoretical model offers a new perspective on PD pathogenesis and potentially novel therapeutic targets aimed at restoring or enhancing metabolic spiking in SNcDA neurons.