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Significance Identifying dysfunctional cellular mechanisms in sporadic neurodegenerative diseases has been challenging. Therefore, in-depth investigation of genetic forms of disease can provide valuable insight into pathogenic disease mechanisms. Here, we demonstrate the novel interaction between two Parkinson’s disease-linked genes, LRRK2 and auxilin. Additionally, as both genes have described roles at the synapse, we identify synaptic dysfunction as a contributor of dopamine-mediated toxic effects in human dopaminergic neurons. Together, these results highlight the importance of the mechanistic dissection of genetic forms of Parkinson’s disease to identify converging pathways and targets for therapeutic intervention.

LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson’s disease