Dopamine, but not glutamate, release is disrupted in Parkinson's patient-derived dopaminergic neurons due to impaired vesicle loading

ABSTRACT

Dopamine release defects are an early and consistently-observed pathological feature of Parkinson’s disease, however the underlying drivers of disease have not yet been elucidated. Here we demonstrate dopamine release is reduced in patient-derived dopamine neurons with the SNCA-triplication mutation and find that this is due to impaired synaptic vesicle loading resulting in reduced dopamine content and increased dopamine turnover while dopamine synthesis remains intact. Supplementation with L-DOPA rescues these observed dopamine release defects. We find that impaired dopamine vesicle loading results in decreased synaptic vesicle pool size. In contrast, glutamate release is intact in Parkinson’s patient neurons, revealing specificity in dopaminergic dysfunction. In combination, these data reveal dopamine loading into synaptic vesicles as a critical target in Parkinson’s disease therapies.

FILE DESCRIPTIONS

This repository contains the following files:

Key Resources Table (.xlsx) - Table containing details on key resources (antibodies, cell lines, and software), and the persistent identifiers for protocols used and generated in this study. 

Source Data Folder (.zip):

_README_Source_Data (.txt) with detailed information about each dataset.

Individual tabular datasets corresponding to each panel shown in the Main Figures 1 to 4 (.csv).

Excel spreadsheet containing all tabular datasets plotted in Main Figures 1 to 4 (.xlsx)

Supplementary Data Folder (.zip):

_README_Supplementary_Data (.txt) with detailed information about each dataset.

Individual tabular datasets corresponding to each panel shown in the Supplementary Figures 1-5 (.csv).

Excel spreadsheet containing all tabular datasets plotted in Supplementary Figures 1-5 (.xlsx)

iPSC Quality Control Table (.xlsx) - Table detailing which quality control tests were performed.