Background: Depletion of putamen dopamine (DA) characterizes Parkinson disease (PD) and precedes the onset of motor symptoms by years. Increasing evidence implicates impaired vesicular sequestration and attenuated detoxification of the toxic catecholaldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL) in disease pathogenesis. We applied a mechanistic kinetic model to examine how perturbations in dopamine handling from DOPAL-induced autotoxicity affect the timing and trajectory of symptomatic PD. Methods: Using an icon-based application we constructed a model of intraneuronal dopamine synthesis, vesicular storage, leakage, metabolism, aldehyde detoxification, delayed toxicity, and a-synuclein modification. Model behavior was evaluated by internal consistency and concordance with empirical cellular, animal, imaging, and post-mortem neurochemical data. We examined predicted effects of genetic variants, acquired factors (e.g., stress, environmental exposures), and treatments on vesicular dopamine content across the lifespan. Results: Without imposing a pre-defined disease curve, the model generated a tri-phasic trajectory of vesicular dopamine loss—homeostasis, dyshomeostasis, and symptomatic decline—from delayed DOPAL-mediated toxicity, with progressive impairment of vesicular sequestration and other intra-neuronal processes. The model predicted that genetic decreases in vesicular uptake or aldehyde detoxification and increases in dopamine biosynthesis would shorten the time to the onset of symptomatic disease, whereas monoamine oxidase inhibition, levodopa, and anti-oxidant treatment applied early and in combination would be protective. Preclinical, multi-target interventions would delay or prevent crossing a symptomatic threshold within the modeled lifespan. Conclusion: Systems modeling across the lifespan predicts a tri-phasic decline in putamen dopamine stores in PD. The timing and combination of interventions may be decisive for delaying or preventing symptomatic disease.
David S. Goldstein (Sat,) studied this question.