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

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....

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Published in:PLoS genetics 2015-09, Vol.11 (9), p.e1005503-e1005503
Main Authors: Imai, Yuzuru, Kobayashi, Yoshito, Inoshita, Tsuyoshi, Meng, Hongrui, Arano, Taku, Uemura, Kengo, Asano, Takeshi, Yoshimi, Kenji, Zhang, Chang-Liang, Matsumoto, Gen, Ohtsuka, Toshiyuki, Kageyama, Ryoichiro, Kiyonari, Hiroshi, Shioi, Go, Nukina, Nobuyuki, Hattori, Nobutaka, Takahashi, Ryosuke
Format: Article
Language:English
Subjects:
Animals
Carrier Proteins - metabolism
Cellular signal transduction
Dopamine - metabolism
Drosophila
Endosomes - metabolism
Genes
Genetic aspects
Guanine Nucleotide Exchange Factors - metabolism
Health aspects
HEK293 Cells
Humans
Kinases
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Mutation
Observations
Parkinson Disease - enzymology
Parkinson's disease
Protein Binding
Protein kinases
Protein-Serine-Threonine Kinases - metabolism
Protein-Serine-Threonine Kinases - physiology
Receptors, Notch - metabolism
Signal Transduction - physiology
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1005503