Figure 3.

PD as a consequence of “multiple hits” or “stochastic acceleration” of an ongoing SNc DA neuron demise throughout the lifetime of a healthy organism. (A) Pre-and perinatal mDA neuron development (indicated by the transition from a proliferating mDA progenitor to a postmitotic mDA precursor to a maturing mDA neuron) endows a healthy human with an average number of 500,000 mDA neurons. Although still debated, a lifelong increased oxidative/nitrosative stress load coupled to a high proteostatic and energetic demand in particularly the SNc DA neurons lead to a continuous demise of some of these neurons (curved blue line) which, however, will not hit the crucial threshold (dashed horizontal black line indicating that only 50% of the mDA neurons remain in the human VM) during the usual human life expectancy. At this threshold, the first PD symptoms would appear (dashed vertical black line), and would worsen with increasing age (dashed pink line). (B) As suggested by the “multiple hit” or “stochastic acceleration” hypotheses, the normal mDA neuron demise (dashed blue line) is accelerated by the impact of diverse genetic and/or environmental stressors throughout the postnatal human lifetime (yellow flash and curved line), and will lead to the appearance of the first symptoms and diagnosis of PD (vertical black line) after reaching the critical threshold of mDA neuron numbers (dashed horizontal black line) in the sixth decade of life, as is the case in most (idiopathic) PD cases. Alternatively or in addition, a faulty pre-/perinatal mDA neuron development (orange flash) will render the individual with an already reduced number of mDA neurons at birth, which is still above the critical threshold and can thus be compensated by a heightened DA signaling and metabolism in the remaining mDA neurons from the human VM. Nevertheless, the normal age-related demise of these neurons, most likely together with additional postnatal impacts including a compromised mDA survival (dashed orange flash), will also lead to a much earlier surpassing of the critical threshold and diagnosis of PD (curved orange line). In both cases and due to the current lack of disease-modifying or-halting treatments, PD symptoms and thus severity of the disease will progressively worsen (pink line). The prodromal and presymptomatic period of life in these individuals (gray box) probably represents the best window of opportunity for the modification or, ideally, prevention of PD. Modified after (Le et al., 2009; Collier et al., 2011; Von Linstow et al., 2020).