Parkinson's disease-linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons

Pingping Song, Wesley Peng, Veronique Sauve, Rayan Fakih, Zhong Xie, Daniel Ysselstein, Talia Krainc, Yvette C. Wong, Niccolò E. Mencacci, Jeffrey N. Savas, D. James Surmeier, Kalle Gehring, Dimitri Krainc*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Parkin-mediated mitophagy has been studied extensively, but whether mutations in parkin contribute to Parkinson's disease pathogenesis through alternative mechanisms remains unexplored. Using patient-derived dopaminergic neurons, we found that phosphorylation of parkin by Ca2+/calmodulin-dependent protein kinase 2 (CaMK2) at Ser9 leads to activation of parkin in a neuronal-activity-dependent manner. Activated parkin ubiquitinates synaptojanin-1, facilitating its interaction with endophilin A1 and synaptic vesicle recycling. Neurons from PD patients with mutant parkin displayed defective recycling of synaptic vesicles, leading to accumulation of toxic oxidized dopamine that was attenuated by boosting endophilin A1 expression. Notably, combined heterozygous parkin and homozygous PTEN-induced kinase 1 (PINK1) mutations led to earlier disease onset compared with homozygous mutant PINK1 alone, further underscoring a PINK1-independent role for parkin in contributing to disease. Thus, this study identifies a pathway for selective activation of parkin at human dopaminergic synapses and highlights the importance of this mechanism in the pathogenesis of Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)3775-3788.e7
JournalNeuron
Volume111
Issue number23
DOIs
StatePublished - Dec 6 2023

Keywords

  • CaMK2-mediated activation of parkin
  • PINK1-independent
  • Parkinson's disease
  • human dopaminergic neurons
  • synaptic dysfunction
  • toxic oxidized dopamine

ASJC Scopus subject areas

  • General Neuroscience

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