The vanishing dopamine 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 mid-brain. The cause of this cell loss is attributed to irreparable damage due to a dysregulation cascade originating from excess cytosolic dopamine[2]. 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 introduce a theory of specialized non-causal action potentials that serve metabolic homeostasis called `metabolic spikes' which can account for spontaneous activity observed in many neuron types including SNcDA. We propose that loss of these metabolic spikes in SNcDA can account for both, the cause of PD and the subsequent dopamine dysregulation. Neurons, presumably in anticipation of synaptic inputs, keep their ATP levels at a maximum such that they are ATP-surplus/ADP-scarce during synaptic quiescence. With ADP availability as the rate-limiting step, ATP production stalls in their mitochondria when energy consumption is low, leading to the formation of toxic Reactive Oxygen Species(ROS). Under these circumstances, `metabolic spikes’ serve to restore ATP production and relieve ROS toxicity. In a metabolism-coupled model of SNcDA that senses ROS and initiates spikes, we identified three categories of deficits that could decrease metabolic spikes and consequently deplete the dopamine tone seen in PD. Importantly in PD, such lowered extracellular dopamine level is misread by D2-autoreceptors and dopamine synthesis is increased. With dopamine vesicles being already full, excess dopamine produces disruptive aldehyde (DOPAL) leading to dysregulation and ultimately cell death. Metabolic spikes, though relevant for cellular health, may thus be an integrated neuronal mechanism that operates in synergy with synaptic integration and forms a basic principle of network dynamics and behaviour, as exemplified in PD.