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タイトル: | The Parkinson's Disease-Associated Protein Kinase LRRK2 Modulates Notch Signaling through the Endosomal Pathway |
著者: | 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 https://orcid.org/0000-0002-5985-1120 (unconfirmed) Kiyonari, Hiroshi Shioi, Go Nukina, Nobuyuki Hattori, Nobutaka Takahashi, Ryosuke https://orcid.org/0000-0002-1407-9640 (unconfirmed) |
著者名の別形: | 大塚, 俊之 影山, 龍一郎 高橋, 良輔 |
発行日: | 10-Sep-2015 |
出版者: | Public Library of Science |
誌名: | PLOS Genetics |
巻: | 11 |
号: | 9 |
論文番号: | e1005503. |
抄録: | 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. |
著作権等: | © 2015 Imai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited |
URI: | http://hdl.handle.net/2433/214275 |
DOI(出版社版): | 10.1371/journal.pgen.1005503 |
PubMed ID: | 26355680 |
出現コレクション: | 学術雑誌掲載論文等 |
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