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. 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.
Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Yuzuru
Y
Imai
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.
Yoshito
Y
Kobayashi
Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Tsuyoshi
T
Inoshita
Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Hongrui
H
Meng
Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Taku
T
Arano
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kengo
K
Uemura
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Takeshi
T
Asano
Department of Neurophysiology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Kenji
K
Yoshimi
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.
Chang-Liang
CL
Zhang
Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Gen
G
Matsumoto
Department of Cell Biology, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Toshiyuki
T
Ohtsuka
Department of Cell Biology, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Ryoichiro
R
Kageyama
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe, Japan.
Hiroshi
H
Kiyonari
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe, Japan.
Go
G
Shioi
Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Nobuyuki
N
Nukina
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.
Nobutaka
N
Hattori
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.
Ryosuke
R
Takahashi
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004330:Drosophila; D011992:Endosomes / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D010300:Parkinson Disease / Q000201:enzymology*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; D051880:Receptors, Notch; C118566:HERC2 protein, human; C575176:Neurl4 protein, human; D044767:Ubiquitin-Protein Ligases; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine