Dopamine release from Parkinson’s patient-derived neurons is disrupted due to impaired synaptic vesicle loading
Output Details
Description
Striatal dopamine release defects are an early pathological feature observed in diverse models of Parkinson’s disease. However, the underlying molecular mechanisms responsible, and potential links to disease aetiology in humans, have been elusive. Here, we tested the hypothesis that dopamine release deficits are a characteristic feature of disease-relevant human neurons, using human Parkinson’s patient iPSC-derived dopamine neurons carrying the *SNCA*-triplication mutation. We reveal deficits in dopamine release from *SNCA*-triplication patient-derived neurons, and identify that this is due to reduced dopamine content arising from a lower capacity to store dopamine through reduced expression and function of vesicular monoamine transporter 2 (VMAT2) compared to healthy controls. In turn, by imaging VMAT substrate FFN206, and reporters for synaptic vesicular dynamics, SynaptopHluorin and CypHer5E, we reveal corresponding deficits in the size of either VMAT-containing, presynaptic releasing or recycling vesicle pools. Consistent with diminished synaptic vesicle loading and recycling, the cytosolic turnover of dopamine indicated by the ratio of concentrations of dopamine metabolite DOPAC to dopamine was elevated. By contrast, glutamate release events and VGLUT2 levels in neurons in the same preparations were not disturbed, demonstrating that vesicular dysfunction is limited to vesicles for dopamine. These findings therefore reveal dopamine loading into vesicles as a locus of dysfunction in human Parkinson’s-derived neurons. These disturbances will not only drive deficits in dopamine release but could potentially also be detrimental to dopamine neuron viability through an increased burden of oxidative stress associated with elevated cytosolic dopamine, thus contributing to both symptoms and aetiology of Parkinson’s pathology and offering a strategic target for improved therapies.
Identifier (DOI)
10.64898/2026.03.11.711038
