한빛사
>
한빛사논문
한빛사논문
- 조회1,830
Nat. Commun., Published 27 August 2018, 9, Article number: 3465 | https://doi.org/10.1038/s41467-018-05958-z
LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation
Eun-Jin Bae1, Dong-Kyu Kim1, Changyoun Kim2,3, Michael Mante3, Anthony Adame3, Edward Rockenstein3, Ayse Ulusoy4, Michael Klinkenberg 4, Ga Ram Jeong5, Jae Ryul Bae5, Cheolsoon Lee6, He-Jin Lee6, Byung-Dae Lee7, Donato A. Di Monte4, Eliezer Masliah2,3,8 & Seung-Jae Lee1,*
1Departments of Biomedical Sciences and Medicine, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea. 2 Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. 3Department Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. 4German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Strasse 27, 53127 Bonn, Germany. 5Department of Neuroscience, Graduate School, Kyung Hee University, Seoul 02447, Korea. 6Department of Anatomy, School of Medicine, Konkuk University, Seoul 05029, Korea. 7Department of Physiology, School of Medicine, Kyung Hee University, Seoul 02447, Korea. 8Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. These authors contributed equally: Eun-Jin Bae, Dong-Kyu Kim.
*Correspondence to Seung-Jae Lee
1Departments of Biomedical Sciences and Medicine, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea. 2 Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. 3Department Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. 4German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Strasse 27, 53127 Bonn, Germany. 5Department of Neuroscience, Graduate School, Kyung Hee University, Seoul 02447, Korea. 6Department of Anatomy, School of Medicine, Konkuk University, Seoul 05029, Korea. 7Department of Physiology, School of Medicine, Kyung Hee University, Seoul 02447, Korea. 8Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. These authors contributed equally: Eun-Jin Bae, Dong-Kyu Kim.
*Correspondence to Seung-Jae Lee
Abstract
Propagation of α-synuclein aggregates has been suggested as a contributing factor in Parkinson’s disease (PD) progression. However, the molecular mechanisms underlying α-synuclein aggregation are not fully understood. Here, we demonstrate in cell culture, nematode, and rodent models of PD that leucine-rich repeat kinase 2 (LRRK2), a PD-linked kinase, modulates α-synuclein propagation in a kinase activity-dependent manner. The PD-linked G2019S mutation in LRRK2, which increases kinase activity, enhances propagation efficiency. Furthermore, we show that the role of LRRK2 in α-synuclein propagation is mediated by RAB35 phosphorylation. Constitutive activation of RAB35 overrides the reduced α-synuclein propagation phenotype in lrk-1 mutant C. elegans. Finally, in a mouse model of synucleinopathy, administration of an LRRK2 kinase inhibitor reduced α-synuclein aggregation via enhanced interaction of α-synuclein with the lysosomal degradation pathway. These results suggest that LRRK2-mediated RAB35 phosphorylation is a potential therapeutic target for modifying disease progression.
논문정보
- Research article
- 2018년 08월 (BRIC 등록일 2018-09-04)
- 국내(교신)+국외 연구진
- 의약학 > 신경의학
댓글 작성 로그인
팝업 닫기관련 링크
연구자 키워드
연구자 ID
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기
