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- Title
Parkinson's Disease-Associated LRRK2 Hyperactive Kinase Mutant Disrupts Synaptic Vesicle Trafficking in Ventral Midbrain Neurons.
- Authors
Ping-Yue Pan; Xianting Li; Jing Wang; Powell, James; Qian Wang; Yuanxi Zhang; Zhaoyu Chen; Wicinski, Bridget; Hof, Patrick; Ryan, Timothy A.; Zhenyu Yue
- 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 LRRK2 G2019S 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 synaptojaninl in vitro, resulting in the disruption of endophilin-synaptojanin 1 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.
- Subjects
PARKINSON'S disease; DARDARIN; SYNAPTIC vesicles; DOPAMINERGIC neurons; SYNAPTOJANINS
- Publication
Journal of Neuroscience, 2017, Vol 37, Issue 47, p11366
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.0964-17.2017