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

Proc Natl Acad Sci U S A. 2018 May 22;115(21):5576-5581. doi: 10.1073/pnas.1717590115. Epub 2018 May 7.


Recently identified Parkinson's disease (PD) genes involved in synaptic vesicle endocytosis, such as DNAJC6 (auxilin), have further implicated synaptic dysfunction in PD pathogenesis. However, how synaptic dysfunction contributes to the vulnerability of human dopaminergic neurons has not been previously explored. Here, we demonstrate that commonly mutated, PD-linked leucine-rich repeat kinase 2 (LRRK2) mediates the phosphorylation of auxilin in its clathrin-binding domain at Ser627. Kinase activity-dependent LRRK2 phosphorylation of auxilin led to differential clathrin binding, resulting in disrupted synaptic vesicle endocytosis and decreased synaptic vesicle density in LRRK2 patient-derived dopaminergic neurons. Moreover, impaired synaptic vesicle endocytosis contributed to the accumulation of oxidized dopamine that in turn mediated pathogenic effects such as decreased glucocerebrosidase activity and increased α-synuclein in mutant LRRK2 neurons. Importantly, these pathogenic phenotypes were partially attenuated by restoring auxilin function in mutant LRRK2 dopaminergic neurons. Together, this work suggests that mutant LRRK2 disrupts synaptic vesicle endocytosis, leading to altered dopamine metabolism and dopamine-mediated toxic effects in patient-derived dopaminergic neurons.

Keywords: DA oxidation; LRRK2; Parkinson’s disease; auxilin; synaptic vesicle endocytosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Auxilins / genetics
  • Auxilins / metabolism*
  • Cells, Cultured
  • Dopamine / pharmacology*
  • Dopamine Agents / pharmacology
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology*
  • Endocytosis / drug effects
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
  • Mutation*
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology*
  • Phosphorylation
  • Synaptic Vesicles / metabolism
  • Synaptic Vesicles / pathology*


  • Auxilins
  • Dopamine Agents
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Dopamine