Format

Send to

Choose Destination
Nat Commun. 2018 Aug 27;9(1):3465. doi: 10.1038/s41467-018-05958-z.

LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation.

Author information

1
Departments 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.
3
Department Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
4
German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Strasse 27, 53127, Bonn, Germany.
5
Department of Neuroscience, Graduate School, Kyung Hee University, Seoul, 02447, Korea.
6
Department of Anatomy, School of Medicine, Konkuk University, Seoul, 05029, Korea.
7
Department of Physiology, School of Medicine, Kyung Hee University, Seoul, 02447, Korea.
8
Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
9
Departments of Biomedical Sciences and Medicine, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, Korea. sjlee66@snu.ac.kr.

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.

PMID:
30150626
PMCID:
PMC6110743
DOI:
10.1038/s41467-018-05958-z
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center