Parkinson’s disease-associated LRRK2 hyperactive kinase mutant disrupts synaptic vesicle trafficking in ventral midbrain neurons

Ping Yue Pan, Xianting Li, Jing Wang, James Powell, Qian Wang, Yuanxi Zhang, Zhaoyu Chen, Bridget Wicinski, Patrick Hof, Timothy A. Ryan, Zhenyu Yue

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

Parkinson’s disease (PD) is characterized pathologically by the selective loss of substantia nigra (SN) dopaminergic (DAergic) neurons. Recent evidence has suggested a role of LRRK2, linked to the most frequent familial PD, in regulating synaptic vesicle (SV) trafficking. However, the mechanism whereby LRRK2 mutants contribute to nigral vulnerability remains unclear. Here we show that the most common PD mutation LRRK2 G2019S impairs SV endocytosis in ventral midbrain (MB) neurons, including DA neurons, and the slowed endocytosis can be rescued by inhibition of LRRK2 kinase activity. A similar endocytic defect, however, was not observed in LRRK2 mutant neurons from the neocortex (hereafter, cortical neurons) or the hippocampus, suggesting a brain region-specific vulnerability to the G2019S mutation. Additionally, we found MB-specific impairment of SV endocytosis in neurons carrying heterozygous deletion of SYNJ1 (PARK20), a gene that is associated with recessive Parkinsonism. Combining SYNJ1+/- and LRRK2G2019S does not exacerbate SV endocytosis but impairs sustained exocytosis in MB neurons and alters specific motor functions of 1-year-old male mice. Interestingly, we show that LRRK2 directly phosphorylates synaptojanin1 in vitro, resulting in the disruption of endophilin-synaptojanin1 interaction required for SV endocytosis. Our work suggests a merge of LRRK2 and SYNJ1 pathogenic pathways in deregulating SV trafficking in MB neurons as an underlying molecular mechanism of early PD pathogenesis.

Original languageEnglish
Pages (from-to)11366-11376
Number of pages11
JournalJournal of Neuroscience
Volume37
Issue number47
DOIs
StatePublished - 22 Nov 2017

Keywords

  • Dopamine neuron
  • Genetic interaction
  • LRRK2 G2019S
  • Parkinson’s disease
  • Synaptic vesicle
  • Synaptojanin1/synj1

Fingerprint

Dive into the research topics of 'Parkinson’s disease-associated LRRK2 hyperactive kinase mutant disrupts synaptic vesicle trafficking in ventral midbrain neurons'. Together they form a unique fingerprint.

Cite this