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PLoS Genet. 2015 Sep 10;11(9):e1005503. doi: 10.1371/journal.pgen.1005503. eCollection 2015 Sep.

The Parkinson's Disease-Associated Protein Kinase LRRK2 Modulates Notch Signaling through the Endosomal Pathway.

Author information

1
Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan.
2
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; CREST (Core Research for Evolutionary Science and Technology), Japan Science and Technology Agency, Saitama, Japan.
3
Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan.
4
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
5
Department of Neurophysiology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
6
Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan.
7
Department of Cell Biology, Institute for Virus Research, Kyoto University, Kyoto, Japan.
8
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe, Japan.
9
Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan; CREST (Core Research for Evolutionary Science and Technology), Japan Science and Technology Agency, Saitama, Japan; Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is a key molecule in the pathogenesis of familial and idiopathic Parkinson's disease (PD). We have identified two novel LRRK2-associated proteins, a HECT-type ubiquitin ligase, HERC2, and an adaptor-like protein with six repeated Neuralized domains, NEURL4. LRRK2 binds to NEURL4 and HERC2 via the LRRK2 Ras of complex proteins (ROC) domain and NEURL4, respectively. HERC2 and NEURL4 link LRRK2 to the cellular vesicle transport pathway and Notch signaling, through which the LRRK2 complex promotes the recycling of the Notch ligand Delta-like 1 (Dll1)/Delta (Dl) through the modulation of endosomal trafficking. This process negatively regulates Notch signaling through cis-inhibition by stabilizing Dll1/Dl, which accelerates neural stem cell differentiation and modulates the function and survival of differentiated dopaminergic neurons. These effects are strengthened by the R1441G ROC domain-mutant of LRRK2. These findings suggest that the alteration of Notch signaling in mature neurons is a component of PD etiology linked to LRRK2.

PMID:
26355680
PMCID:
PMC4565672
DOI:
10.1371/journal.pgen.1005503
[Indexed for MEDLINE]
Free PMC Article

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