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.

Details

Title
LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation
Author
Eun-Jin Bae 1 ; Dong-Kyu, Kim 1 ; Kim, Changyoun 2 ; Mante, Michael 3 ; Adame, Anthony 3 ; Rockenstein, Edward 3 ; Ulusoy, Ayse 4 ; Klinkenberg, Michael 4   VIAFID ORCID Logo  ; Ga Ram Jeong 5 ; Bae, Jae Ryul 5 ; Lee, Cheolsoon 6 ; He-Jin, Lee 6 ; Lee, Byung-Dae 7 ; Di Monte, Donato A 4 ; Masliah, Eliezer 8 ; Lee, Seung-Jae 1 

1  Departments of Biomedical Sciences and Medicine, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea 
2  Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA 
3  Department Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA 
4  German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany 
5  Department of Neuroscience, Graduate School, Kyung Hee University, Seoul, Korea 
6  Department of Anatomy, School of Medicine, Konkuk University, Seoul, Korea 
7  Department of Physiology, School of Medicine, Kyung Hee University, Seoul, Korea 
8  Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA, USA 
Pages
1-16
Publication year
2018
Publication date
Aug 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-05958-z
ProQuest document ID
2094416419
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.