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:10.1371/journal.pgen.1005503

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

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

Authors

Yuzuru Imai¹, Yoshito Kobayashi², Tsuyoshi Inoshita¹, Hongrui Meng³, Taku Arano¹, Kengo Uemura⁴, Takeshi Asano⁴, Kenji Yoshimi⁵, Chang-Liang Zhang², Gen Matsumoto⁶, Toshiyuki Ohtsuka⁷, Ryoichiro Kageyama⁷, Hiroshi Kiyonari⁸, Go Shioi⁸, Nobuyuki Nukina⁶, Nobutaka Hattori⁹, Ryosuke Takahashi²

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
Protein Serine-Threonine Kinases / physiology*
Receptors, Notch / metabolism*
Signal Transduction / physiology*
Ubiquitin-Protein Ligases

Substances

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

Grants and funding

This work was supported by the Grant-in-Aid for Scientific Research 21790302 (YI) from JSP in Japan (https://www.jsps.go.jp/english/e-grants/), the Cell Science Research Foundation (YI)(http://www.shionogi.co.jp/zaidan/), the CREST program of JST in Japan (RT, NH)(http://www.jst.go.jp/kisoken/crest/en/about/basic.html), Grant-in-Aid for Scientific Research on Innovative Areas 23110502, 23110507, 23110518 (YI, RT, NH) from the MEXT in Japan (http://www.tmd.ac.jp/mri/shingakujutu/index-e.html), and Grant-in-Aid for Science Research 201324018A from the MHLW in Japan (RT)(http://www.mhlw.go.jp/stf/seisakunitsuite/bunya/hokabunya/kenkyujigyou/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.