PLoS Genetics (Sep 2015)

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

  • Yuzuru 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

DOI
https://doi.org/10.1371/journal.pgen.1005503
Journal volume & issue
Vol. 11, no. 9
p. e1005503

Abstract

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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.