LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation

Eun-Jin Bae, Dong-Kyu Kim, Changyoun Kim, Michael Mante, Anthony Adame, Edward Rockenstein, Ayse Ulusoy, Michael Klinkenberg, Ga Ram Jeong, Jae Ryul Bae, Cheolsoon Lee, He-Jin Lee, Byung-Dae Lee, Donato A. Di Monte, Eliezer Masliah and Seung-Jae Lee ()
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Eun-Jin Bae: Seoul National University College of Medicine, Departments of Biomedical Sciences and Medicine, Neuroscience Research Institute
Dong-Kyu Kim: Seoul National University College of Medicine, Departments of Biomedical Sciences and Medicine, Neuroscience Research Institute
Changyoun Kim: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Molecular Neuropathology Section
Michael Mante: School of Medicine, University of California, San Diego, Department Neurosciences
Anthony Adame: School of Medicine, University of California, San Diego, Department Neurosciences
Edward Rockenstein: School of Medicine, University of California, San Diego, Department Neurosciences
Ayse Ulusoy: German Center for Neurodegenerative Diseases (DZNE)
Michael Klinkenberg: German Center for Neurodegenerative Diseases (DZNE)
Ga Ram Jeong: Graduate School, Kyung Hee University, Department of Neuroscience
Jae Ryul Bae: Graduate School, Kyung Hee University, Department of Neuroscience
Cheolsoon Lee: School of Medicine, Konkuk University, Department of Anatomy
He-Jin Lee: School of Medicine, Konkuk University, Department of Anatomy
Byung-Dae Lee: School of Medicine, Kyung Hee University, Department of Physiology
Donato A. Di Monte: German Center for Neurodegenerative Diseases (DZNE)
Eliezer Masliah: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Molecular Neuropathology Section
Seung-Jae Lee: Seoul National University College of Medicine, Departments of Biomedical Sciences and Medicine, Neuroscience Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05958-z

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