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

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.
AuthorsYuzuru Imai, Yoshito Kobayashi, Tsuyoshi Inoshita, Hongrui Meng, Taku Arano, Kengo Uemura, Takeshi Asano, Kenji Yoshimi, Chang-Liang Zhang, Gen Matsumoto, Toshiyuki Ohtsuka, Ryoichiro Kageyama, Hiroshi Kiyonari, Go Shioi, Nobuyuki Nukina, Nobutaka Hattori, Ryosuke Takahashi
JournalPLoS genetics (PLoS Genet) Vol. 11 Issue 9 Pg. e1005503 (Sep 2015) ISSN: 1553-7404 [Electronic] United States
PMID26355680 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carrier Proteins
  • Guanine Nucleotide Exchange Factors
  • Receptors, Notch
  • HERC2 protein, human
  • Neurl4 protein, human
  • Ubiquitin-Protein Ligases
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases
  • Dopamine
Topics
  • Animals
  • Carrier Proteins (metabolism)
  • Dopamine (metabolism)
  • Drosophila
  • Endosomes (metabolism)
  • Guanine Nucleotide Exchange Factors (metabolism)
  • HEK293 Cells
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Parkinson Disease (enzymology)
  • Protein Binding
  • Protein Serine-Threonine Kinases (metabolism, physiology)
  • Receptors, Notch (metabolism)
  • Signal Transduction (physiology)
  • Ubiquitin-Protein Ligases

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