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

• Published in: PLoS genetics Vol. 11; no. 9; p. 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: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2015; Public Library of Science (PLoS)
• 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
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1005503

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.